Indolizine compounds, a process for their preparation and pharmaceutical compositions containing them

ABSTRACT

Compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein R a , R b , R c , R d , R 1 , R 2 , R 3 , R 4 , R 5 , X, Y and Het are as defined in the description. 
     Medicinal products containing the same which are useful in treating pathologies involving a deficit in apoptosis, such as cancer, auto-immune diseases, and diseases of the immune system.

The present invention relates to new indolizine compounds, to a processfor their preparation and to pharmaceutical compositions containingthem.

The compounds of the present invention are new and have very valuablepharmacological characteristics in the field of apoptosis andcancerology.

Apoptosis, or programmed cell death, is a physiological process that iscrucial for embryonic development and maintenance of tissue homeostasis.

Apoptotic-type cell death involves morphological changes such ascondensation of the nucleus, DNA fragmentation and also biochemicalphenomena such as the activation of caspases which cause damage to keystructural components of the cell, so inducing its disassembly anddeath. Regulation of the process of apoptosis is complex and involvesthe activation or repression of several intracellular signallingpathways (Cory S. et al., Nature Review Cancer, 2002, 2, 647-656).

Deregulation of apoptosis is involved in certain pathologies. Increasedapoptosis is associated with neurodegenerative diseases such asParkinson's disease, Alzheimer's disease and ischaemia. Conversely,deficits in the implementation of apoptosis play a significant role inthe development of cancers and their chemoresistance, in auto-immunediseases, inflammatory diseases and viral infections. Accordingly,absence of apoptosis is one of the phenotypic signatures of cancer(Hanahan D. et al., Cell 2000, 100, 57-70).

The anti-apoptotic proteins of the Bcl-2 family are associated withnumerous pathologies. The involvement of proteins of the Bcl-2 family isdescribed in numerous types of cancer, such as colon cancer, breastcancer, small-cell lung cancer, non-small-cell lung cancer, bladdercancer, ovarian cancer, prostate cancer, chronic lymphoid leukaemia,follicular lymphoma, myeloma, prostate cancer, etc. Overexpression ofthe anti-apoptotic proteins of the Bcl-2 family is involved intumorigenesis, in resistance to chemotherapy and in the clinicalprognosis of patients affected by cancer. There is, therefore, atherapeutic need for compounds that inhibit the anti-apoptotic activityof the proteins of the Bcl-2 family.

In addition to being new, the compounds of the present invention havepro-apoptotic properties making it possible to use them in pathologiesinvolving a defect in apoptosis, such as, for example, in the treatmentof cancer and of immune and auto-immune diseases.

The present invention relates more especially to compounds of formula(I):

wherein:

-   -   X and Y represent a carbon atom or a nitrogen atom, it being        understood that they may not simultaneously represent two carbon        atoms or two nitrogen atoms,    -   the Het moiety of the group

-   -    represents an optionally substituted, aromatic or non-aromatic        ring composed of 5, 6 or 7 ring members, which may contain, in        addition to the nitrogen represented by X or by Y, from one to 3        hetero atoms selected independently from oxygen, sulphur and        nitrogen, it being understood that the nitrogen in question may        be substituted by a group representing a hydrogen atom, a linear        or branched (C₁-C₆)alkyl group or a group —C(O)—O-Alk wherein        Alk is a linear or branched (C₁-C₆)alkyl group,    -   R₁ and R₂ independently of one another represent a hydrogen atom        or a linear or branched (C₁-C₆)alkyl group,    -   or R₁ and R₂ form with the nitrogen atom carrying them a        heterocycloalkyl composed of from 4 to 7 ring members, which may        contain, in addition to the nitrogen atom, another hetero atom        selected from oxygen, sulphur, SO₂ and NR wherein R represents a        hydrogen atom, a linear or branched (C₁-C₆)alkyl group, a        (C₁-C₆)alkylsulphonyl group, a linear or branched        (C₁-C₆)polyhaloalkyl group or a group —C(O)—O-Alk wherein Alk is        a linear or branched (C₁-C₆)alkyl group,    -   R₃ represents a linear or branched (C₁-C₆)alkyl group, a        (C₂-C₆)alkenyl group, a (C₂-C₆)alkynyl group, a cycloalkyl        group, a (C₄-C₁₀)cycloalkyl-(C₁-C₆)alkyl group wherein the alkyl        group may be linear or branched, an aryl group or a heteroaryl        group,    -   R₄ represents an aryl, heteroaryl, cycloalkyl or linear or        branched (C₁-C₆)alkyl group,    -   R₅ represents a hydrogen atom or a halogen atom,    -   R_(a), R_(b), R, and R_(d) independently of one another        represent a hydrogen atom, a halogen atom, a linear or branched        (C₁-C₆)alkyl group, a linear or branched (C₁-C₆)alkoxy group, a        hydroxy group, a linear or branched (C₁-C₆)polyhaloalkyl group,        or a trifluoromethoxy group, or the substituents of one of the        pairs (R_(a),R_(b)), (R_(b),R_(c)) or (R_(c),R_(d)) form        together with the carbon atoms carrying them a ring composed of        from 5 to 7 ring members, which may contain from one to 3 hetero        atoms selected from oxygen, sulphur and nitrogen, it being        understood that the nitrogen in question may be substituted by a        group representing a hydrogen atom, a linear or branched        (C₁-C₆)alkyl group or a group —C(O)—O-Alk wherein Alk is a        linear or branched (C₁-C₆)alkyl group, it also being understood        that one or more carbon atoms of the ring defined hereinbefore        may be deuterated,        it being understood that:    -   “aryl” means a phenyl, naphthyl, biphenyl or indenyl group,    -   “heteroaryl” means any mono- or bi-cyclic group composed of from        5 to 10 ring members, having at least one aromatic moiety and        containing from 1 to 3 hetero atoms selected from oxygen,        sulphur and nitrogen,    -   “cycloalkyl” means any mono- or bi-cyclic non-aromatic        carbocyclic group containing from 4 to 10 ring members,        it being possible for the alkyl, aryl, heteroaryl, cycloalkyl        and heterocycloalkyl groups so defined to be substituted by from        1 to 3 groups selected from optionally substituted linear or        branched (C₁-C₆)alkyl, (C₃-C₆)spiro, linear or branched        (C₁-C₆)alkoxy, (C₁-C₆)alkyl-S—, hydroxy, oxo (or N-oxide where        appropriate), nitro, cyano, —COOR′, NR′R″, linear or branched        (C₁-C₆)polyhaloalkyl, trifluoromethoxy, (C₁-C₆)alkylsulphonyl or        halogen, it being understood that R′ and R″ independently of one        another represent a hydrogen atom or a linear or branched        (C₁-C₆)alkyl group,        it being possible for the Het moiety of the group

defined hereinbefore to be substituted by a group selected from linearor branched (C₁-C₆)alkyl, hydroxy, NR₁′R₁″ and halogen, it beingunderstood that R₁′ and R₁″ have the same definitions than the groups R′and R″ mentioned hereinbefore,to their enantiomers and diastereoisomers, and to addition salts thereofwith a pharmaceutically acceptable acid or base.

Among the pharmaceutically acceptable acids there may be mentioned,without implying any limitation, hydrochloric acid, hydrobromic acid,sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid,lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid,fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid,oxalic acid, methanesulphonic acid, camphoric acid etc.

Among the pharmaceutically acceptable bases there may be mentioned,without implying any limitation, sodium hydroxide, potassium hydroxide,triethylamine, tert-butylamine etc.

The group:

advantageously represents one of the following groups:5,6,7,8-tetrahydroindolizine optionally substituted by a hydroxy,indolizine, 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine, tert-butyl3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate,3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine, 2,3-dihydro-1H-pyrrolizineoptionally substituted by a hydroxy,6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine or pyrrolo[1,2-a]pyrazine.

In the preferred compounds of the invention, R₁ and R₂ each representsan alkyl group optionally substituted by a methoxy, or R₁ and R₂ formwith the nitrogen atom carrying them a heterocycloalkyl selected fromthe following groups: morpholine optionally substituted by one or morelinear or branched (C₁-C₆)alkyl(s), oxidomorpholine, thiomorpholine1,1-dioxide, 1,4-oxazepan, 3-methoxypyrrolidine,3,3-difluoropyrrolidine, 3-methoxyazetidine, 3-fluoroazetidine,oxopiperazine or piperazine, the last two groups being substituted by alinear or branched (C₁-C₆)alkyl group, a linear or branched(C₁-C₆)-polyhaloalkyl group or a methylsulphonyl group.

Preferably, R_(a) and R_(d) each represents a hydrogen atom and(R_(b),R_(c)) form together with the carbon atoms carrying them a1,3-dioxolane group wherein one of the carbon atoms is optionallydeuterated, a 1,4-dioxane group, a 1,4-dioxepane group, or R_(a), R_(c)and R_(d) each represents a hydrogen atom and R_(b) represents ahalogen, a methyl, a methoxy, an ethoxy, a trifluoromethyl or atrifluoromethoxy.

The preferred group R₄ is a 4-hydroxyphenyl, 3-fluoro-4-hydroxyphenyl or5-hydroxypyrimidine.

In the preferred compounds, R₃ represents a group selected from phenyl,indole, indoline, 1,2,3,4-tetrahydroquinoline,3,4-dihydro-2H-1,4-benzoxazine, indane, 1H-indazole,1H-pyrrolo[2,3-b]pyridine, pyrimidine, cyclobutylmethyl,cyclopropylmethyl, 1H-pyrazole, pyridine, pyridazine, those groupsoptionally having one or more substituents selected from halogen, linearor branched (C₁-C₆)alkyl, cyano and linear or branched (C₁-C₆)-alkoxy.

The preferred compounds of the invention are listed below:

-   N-(4-hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-N-phenyl-5,6,7,8-tetrahydro-1-indolizine    carboxamide,-   3-{5-chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)-carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-5,6,7,8-tetrahydro-1-indolizine    carboxamide,-   N-(4-hydroxyphenyl)-N-(1-methyl-1H-indazol-5-yl)-3-{2,2-dideuterio-6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizine    carboxamide,-   N-(4-hydroxyphenyl)-N-(1-methyl-1H-indazol-5-yl)-3-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamide,-   N-(4-hydroxyphenyl)-3-{7-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-2,3-dihydro-1,4-benzodioxin-6-yl}-N-phenyl-5,6,7,8-tetrahydro-1-indolizine    carboxamide,-   N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-3-{6-[((3S)-3-[(4-methyl-1-piperazinyl)methyl]-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-1-indolizine    carboxamide,-   N-[4-(hydroxy)phenyl]-N-(1-methyl-1H-indol-5-yl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizine    carboxamide,-   N-(4-hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-N-phenyl-1-indolizine    carboxamide,-   3-{5-chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-1-indolizine    carboxamide,-   6-{5-chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)-carbonyl]phenyl}-N-(3-fluoro-4-methylphenyl)-N-(4-hydroxyphenyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide,-   3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamide,-   N-(3-fluoro-4-methylphenyl)-N-(4-hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizine    carboxamide,-   N-[4-(hydroxy)phenyl]-N-(1-methyl-2,3-dihydro-1H-indol-5-yl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizine    carboxamide,-   3-{5-chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-2,3-dihydro-1H-indol-5-yl)-5,6,7,8-tetrahydro-1-indolizine    carboxamide,-   N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-1-indolizine    carboxamide,-   3-{5-chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)-carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-2,3-dihydro-1H-indol-5-yl)-1-indolizine    carboxamide,-   6-{5-chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)-carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c]-[1,4]oxazine-8-carboxamide,-   N-(3-fluorophenyl)-N-(4-hydroxyphenyl)-3-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamide,    their enantiomers and diastereoisomers, and addition salts thereof    with a pharmaceutically acceptable acid or base.

The invention relates also to a process for the preparation of compoundsof formula (I), which process is characterised in that there is used asstarting material the compound of formula (II):

wherein R_(a), R_(b), R_(c) and R_(d) are as defined for formula (I),which compound of formula (II) is subjected to a Heck reaction, in anaqueous or organic medium, in the presence of a palladium catalyst, of abase, of a phosphine and of the compound of formula (III):

wherein the groups X, Y and Het are as defined for formula (I),to obtain the compound of formula (IV):

wherein R_(a), R_(b), R_(c), R_(d), X, Y and Het are as defined forformula (I),the aldehyde function of which compound of formula (IV) is oxidised tothe carboxylic acid to form the compound of formula (V):

wherein R_(a), R_(b), R_(c), R_(d), X, Y and Het are as defined forformula (I),which compound of formula (V) is then subjected to peptide coupling witha compound of formula (VI):

wherein R₁, R₂ and R₅ are as defined for formula (I),to yield the compound of formula (VII):

wherein R_(a), R_(b), R_(c), R_(d), R₁, R₂, R₅, X, Y and Het are asdefined for formula (I),the ester function of which compound of formula (VII) is hydrolysed toyield the carboxylic acid or the corresponding carboxylate, which may beconverted into an acid derivative such as acyl chloride or thecorresponding anhydride before being coupled with an amine NHR₃R₄wherein R₃ and R₄ have the same meanings as for formula (I), to yieldthe compound of formula (I),which compound of formula (I) may be purified according to aconventional separation technique, which is converted, if desired, intoits addition salts with a pharmaceutically acceptable acid or base andwhich is optionally separated into its isomers according to aconventional separation technique,it being understood that at any moment considered appropriate during thecourse of the process described above, some groups (hydroxy, amino . . .) of the starting reagents or of the synthesis intermediates can beprotected and subsequently deprotected, as required by the synthesis,

More particularly, when one of the groups R₃ or R₄ of the amine NHR₃R₄is substituted by a hydroxy function, the latter may be subjectedbeforehand to a protection reaction prior to coupling with thecarboxylic acid formed from the compound of formula (VII), or with acorresponding acid derivative thereof, the resulting protected compoundof formula (I) subsequently undergoes a deprotection reaction and isthen optionally converted into one of its addition salts with apharmaceutically acceptable acid or base.

The compounds of formulae (II), (III), (VI) and the amine NHR₃R₄ areeither commercially available or can be obtained by the person skilledin the art using conventional chemical reactions described in theliterature.

Pharmacological study of the compounds of the invention has shown thatthey have pro-apoptotic properties. The ability to reactivate theapoptotic process in cancerous cells is of major therapeutic interest inthe treatment of cancers and of immune and auto-immune diseases.

More especially, the compounds according to the invention will be usefulin the treatment of chemo- or radio-resistant cancers, and in malignanthaemopathies and small-cell lung cancer.

Among the cancer treatments envisaged there may be mentioned, withoutimplying any limitation, cancers of the bladder, brain, breast anduterus, chronic lymphoid leukaemias, cancer of the colon, oesophagus andliver, lymphoblastic leukaemias, follicular lymphomas, melanomas,malignant haemopathies, myelomas, ovarian cancer, non-small-cell lungcancer, prostate cancer and small-cell lung cancer.

The present invention relates also to pharmaceutical compositionscomprising at least one compound of formula (I) in combination with oneor more pharmaceutically acceptable excipients.

Among the pharmaceutical compositions according to the invention theremay be mentioned more especially those that are suitable for oral,parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocularor respiratory administration, especially tablets or drages, sublingualtablets, sachets, paquets, capsules, glossettes, lozenges,suppositories, creams, ointments, dermal gels, and drinkable orinjectable ampoules.

The dosage varies according to the sex, age and weight of the patient,the administration route, the nature of the therapeutic indication, orof any associated treatments, and ranges from 0.01 mg to 1 g per 24hours in one or more administrations.

Furthermore, the present invention relates also to the association of acompound of formula (I) with an anticancer agent selected from genotoxicagents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinaseinhibitors and antibodies, and also to pharmaceutical compositionscomprising that type of association and their use in the manufacture ofmedicaments for use in the treatment of cancer.

The compounds of the invention may also be used in association withradiotherapy in the treatment of cancer.

The following Preparations and Examples illustrate the invention but donot limit it in any way.

PREPARATION 16-[1-(Methoxycarbonyl)-5,6,7,8-tetrahydro-3-indolizinyl]-1,3-benzodioxole-5-carboxylicacid Step A: 1-Formyl-2-piperidinecarboxylic acid

To a solution of 40 g of a racemic mixture of 2-piperidinecarboxylicacid (0.310 mmol) in 300 mL of formic acid at 0° C. there are addeddropwise 200 mL (2.15 mmol) of acetic anhydride. The whole is thenstirred at ambient temperature overnight. The reaction mixture is thencooled to 0° C., hydrolysed by the addition of 250 mL of water andstirred for half an hour at 0° C. before being concentrated to dryness.The oil so obtained is taken up in 200 mL of methanol and thenconcentrated to dryness. The title product is obtained in the form of anoil with a yield of 98%. It is used directly, without furtherpurification, for the following step.

¹H-NMR: δ (400 MHz; dmso-d6; 300° K): 13.0 (m, 1H OH); 8.0-8.05 (2s, 1Haldehyde); 4.9-4.5 (2d, 1H α of N and COOH); 4.1-2.6 (m, 2H to α of N);2.2-1.2 (m, 6H piperidine).

IR: ν: —OH: 2000-3000 cm⁻¹ acid; ν: >C═O 1703 cm⁻¹ broad band.

Step B: Methyl 5,6,7,8-tetrahydro-1-indolizinecarboxylate

To a solution of 10 g of carboxylic acid obtained in Step A (63.6 mmol)in 65 mL of dichloroethane there are added in succession 13.4 g of tosylchloride (70.4 mmol), 11.5 mL of methyl 2-chloroacrylate (113.5 mmol)and then, dropwise, 17.8 mL of N,N,N-triethylamine (127.2 mmol). Thereaction mixture is then refluxed for 1.5 hours. It is then brought toambient temperature, and then 5 mL of methyl 2-chloroacrylate (48.9mmol) and, dropwise, 9 mL of N,N,N-triethylamine (64 mmol) are added.The whole is heated at reflux overnight.

The reaction mixture is subsequently diluted with methylene chloride,washed in succession with a 1N HCl solution, a saturated NaHCO₃ solutionand then a saturated NaCl solution until a neutral pH is obtained. Theorganic phase is then dried over MgSO₄, filtered, concentrated todryness, and purified by chromatography over silica gel (heptane/AcOEtgradient). The title product is obtained in the form of an oil.

¹H-NMR: δ (400 MHz; CDCl₃; 300° K): 6.55-6.40 (d, 2H,tetrahydroindolizine); 3.91 (t, 3H methyl ester); 3.78 (s, 3Htetrahydroindolizine); 3.08 (t, 2H, tetrahydroindolizine); 1.95-1.85 (m,4H, tetrahydroindolizine)

IR: ν: >C═O 1692 cm⁻¹ ester

Step C: Methyl3-(6-formyl-1,3-benzodioxol-5-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxylate

To a solution of 6.4 g of the ester obtained in Step B (35.7 mmol) in 12mL of N,N-dimethylacetamide there are added in succession 12.3 g of6-bromo-1,3-benzodioxole-5-carbaldehyde (53.6 mmol) and 7 g of potassiumacetate (71.4 mmol), and the whole is then stirred under argon for 20minutes. 1.3 g of palladium catalyst PdCl₂(PPh₃)₂ (1.8 mmol) are thenadded. The reaction mixture is subsequently heated at 130° C. for onehour before 139 μL of H₂O are added thereto. Heating is maintained atthat same temperature overnight. The mixture is allowed to return toambient temperature and is then diluted with AcOEt. Animal charcoal isadded (2 g per g of product) and the whole is stirred at ambienttemperature for one hour and then filtered. The organic phase is thenwashed with water, dried over magnesium sulphate and concentrated todryness. The crude product so obtained is purified on silica gel(heptane/AcOEt gradient). The title product is obtained in the form ofan oil.

¹H-NMR: δ: (400 MHz; dmso-d6; 353° K): 9.65 (s, 1H, H aldehyde);7.3-7.15 (2s, 2H, H aromatic); 6.45 (s, 1H tetrahydroindolizine); 6.20(s, 2H methylenedioxy); 3.70 (s, 3H methyl ester); 3.5-4.0 (m, 2Htetrahydroindolizine); 3.05 (m, 2H tetrahydroindolizine); 1.85 (m, 4Htetrahydroindolizine)

IR: ν: >C═O 1695 cm⁻¹ ester; ν: >C═O 1674 cm⁻¹

Step D:6-[1-(Methoxycarbonyl)-5,6,7,8-tetrahydro-3-indolizinyl]-1,3-benzodioxole-5-carboxylicacid

There is prepared a solution containing 3.37 g of the compound obtainedin Step C (10.3 mmol) in 9.3 mL of acetone and 8.8 mL (80.24 mmol) of2-methyl-2-butene, which solution is placed at 0° C. There are added,dropwise, 9.3 mL of an aqueous solution containing a mixture of 3.3 g ofNaClO₂ (36.05 mmol) and 3.6 g of Na₂PO₄ (25.75 mmol). The whole issubsequently stirred at ambient temperature for 7 hours. The reactionmixture is then concentrated in order to remove the acetone. The solidthen obtained is filtered, washed with water and then dried in vacuo at40° C. overnight. The title product is obtained in the form of a solid,which is used subsequently without being purified further.

¹H-NMR: δ (400 MHz; dmso-d6; 300° K): 12.10 (m, 1H, H carboxylic acid);7.40-6.88 (2s, 2H, H aromatic); 6.20 (s, 1H, H tetrahydroindolizine);6.18 (s, 2H, H methylenedioxy); 3.70 (s, 3H, methyl ester); 3.55 (t, 2Htetrahydroindolizine); 3.00 (t, 2H tetrahydroindolizine); 1.80 (m, 4H, Htetrahydroindolizine)

IR: ν: —OH: 3000-2000 cm⁻¹ acid; ν: >C═O 1686-1676 cm⁻¹ ester+acid;ν: >C═C<1608 cm⁻¹

PREPARATION 24-Bromo-2-[1-(methoxycarbonyl)-5,6,7,8-tetrahydro-3-indolizin]-benzoicacid

The procedure is as in the process of Preparation 1, replacing the6-bromo-1,3-benzodioxole-5-carbaldehyde used in Step C by2,4-dibromobenzaldehyde. There is obtained a mixture of tworegioisomers, which are separated by chromatography.

PREPARATION 34-Chloro-2-[1-(methoxycarbonyl)-5,6,7,8-tetrahydro-3-indolizinyl]-benzoicacid

The procedure is as in the process of Preparation 1, replacing the6-bromo-1,3-benzodioxole-5-carbaldehyde used in Step C by2-bromo-4-chlorobenzaldehyde.

PREPARATION 44-Fluoro-2-[1-(methoxycarbonyl)-5,6,7,8-tetrahydro-3-indolizinyl]-benzoicacid

The procedure is as in the process of Preparation 1, replacing the6-bromo-1,3-benzodioxole-5-carbaldehyde used in Step C by2-bromo-4-fluorobenzaldehyde.

PREPARATION 58-[1-(Methoxycarbonyl)-5,6,7,8-tetrahydro-3-indolizinyl]-3,4-dihydro-2H-1,5-benzodioxepine-7-carboxylicacid

The procedure is as in the process of Preparation 1, replacing the6-bromo-1,3-benzodioxole-5-carbaldehyde used in Step C by8-bromo-3,4-dihydro-2H-1,5-benzodioxepine-7-carbaldehyde.

PREPARATION 64-Methoxy-2-[1-(ethoxycarbonyl)-5,6,7,8-tetrahydro-3-indolizinyl]-benzoicacid

The procedure is as in the process of Preparation 1, replacing the6-bromo-1,3-benzodioxole-5-carbaldehyde used in Step C by2-bromo-4-methoxybenzaldehyde.

PREPARATION 77-[1-(Methoxycarbonyl)-5,6,7,8-tetrahydro-3-indolizinyl]-2,3-dihydro-1,4-benzodioxine-6-carboxylicacid

The procedure is as in the process of Preparation 1, replacing the6-bromo-1,3-benzodioxole-5-carbaldehyde used in Step C by7-bromo-2,3-dihydro-1,4-benzodioxine-6-carbaldehyde.

PREPARATION 84-Ethoxy-2-[1-(methoxycarbonyl)-5,6,7,8-tetrahydro-3-indolizinyl]-benzoicacid

The procedure is as in the process of Preparation 1, replacing the6-bromo-1,3-benzodioxole-5-carbaldehyde used in Step C by2-bromo-4-ethoxybenzaldehyde.

PREPARATION 92,2-Dideuterio-6-[1-(methoxycarbonyl)-5,6,7,8-tetrahydro-3-indolizinyl]-1,3-benzodioxole-5-carboxylicacid Step A: 2,2-Dideuterio-1,3-benzodioxole-5-carbaldehyde

To a solution of 30 g of 3,4-dihydroxybenzaldehyde (217 mmol) in 110 mLof anhydrous DMF there are added in succession 114 g of caesiumcarbonate (347 mmol) and 22 mL of dideuterated methylene chloride (347mmol). The reaction mixture is subsequently stirred at ambienttemperature overnight. After filtering off the insoluble portion overCelite, the residual filtrate is subsequently hydrolysed by addition of200 mL of water and then extracted with ethyl acetate. The organicphases are then combined, washed with a saturated LiCl solution and thendried over MgSO₄. After concentration to dryness, the residue ispurified by chromatography over silica gel (petroleum ether/AcOEtgradient). The title product is obtained in the form of a solid.

¹H-NMR: δ: (400 MHz; dmso-d6; 300° K): 9.8 (s, 1H, H aldehyde); 7.4-6.95(m, 3H, H aromatic)

IR: ν: C═O aldehyde: 1670 cm⁻¹

Step B: 6-Bromo-2,2-dideuterio-1,3-benzodioxole-5-carbaldehyde

To a solution of 10 g of the compound obtained in Step A (65.7 mmol) in100 mL of methanol cooled to 0° C. there are added dropwise 3.7 mL of asolution of bromine (1.1 molar equivalents) in 10 mL of methanol. Thewhole is subsequently stirred at ambient temperature overnight. Thereaction mixture is concentrated to dryness and then taken up in water.After stirring, the resulting solid is subsequently filtered and thendried.

¹H-NMR: δ (400 MHz; dmso-d6; 300° K): 10.2 (s, 1H, H aldehyde); 7.4 (s,1H, H aromatic); 7.05 (s, 1H, H aromatic)

IR: ν: C═O aldehyde: 1670 cm⁻¹; C═C aromatic: 1611 cm⁻¹

Step C:2,2-Dideuterio-6-[1-(methoxycarbonyl)-5,6,7,8-tetrahydro-3-indolizinyl]-1,3-benzodioxole-5-carboxylicacid

The procedure is as in the protocol described in Steps C and D ofPreparation 1, replacing the 6-bromo-1,3-benzodioxole-5-carbaldehydeused in Step C by6-bromo-2,2-dideuterio-1,3-benzodioxole-5-carbaldehyde.

PREPARATION 102-[1-(Methoxycarbonyl)-5,6,7,8-tetrahydro-3-indolizinyl]-4-(trifluoromethyl)benzoicacid

The procedure is as in the protocol described in Preparation 1,replacing the 6-bromo-1,3-benzodioxole-5-carbaldehyde used in Step C by2-bromo-4-(trifluoromethyl)benzaldehyde.

PREPARATION 112-[1-(Methoxycarbonyl)-5,6,7,8-tetrahydro-3-indolizinyl]-4-(trifluoromethoxy)benzoicacid

The procedure is as in the protocol described in Preparation 1,replacing the 6-bromo-1,3-benzodioxole-5-carbaldehyde used in Step C by2-bromo-4-(trifluoromethoxy)-benzaldehyde.

PREPARATION 122-[1-(Methoxycarbonyl)-5,6,7,8-tetrahydro-3-indolizinyl]benzoic acid

The procedure is as in the protocol described in Preparation 1,replacing the 6-bromo-1,3-benzodioxole-5-carbaldehyde used in Step C by2-bromobenzaldehyde.

PREPARATION 136-[1-(Methoxycarbonyl)-3-indolizinyl]-1,3-benzodioxole-5-carboxylic acidStep A: 1-(Carboxymethyl)-1,2-dihydropyridinium bromide

To a solution of 16.2 mL of pyridine (200 mmol) in 120 mL of ethylacetate there are added in portions 27.8 g (200 mmol) of bromoaceticacid. The whole is subsequently stirred at ambient temperatureovernight. The precipitate so obtained is filtered off and then washedwith cold ethyl acetate. After drying, the title product is obtained inthe form of a powder, which is used directly for the following step.

¹H-NMR: δ (400 MHz; dmso-d6; 300° K): 9.15 (d, 2H, H aromaticpyridine)); 8.7 (t, 1H, H aromatic); 8.25 (t, 2H, H aromatic); 5.65 (s,2H, H CH₂COOH)

IR: ν: C═O: 1732 cm⁻¹; —OH acid: 2800 cm⁻¹

Step B: Methyl 1-indolizinecarboxylate

To a suspension of 6.55 g of the pyridinium salt obtained in Step A (30mmol) in 240 mL of toluene there are added in succession 16.7 mL ofmethyl acrylate (150 mmol), 4.2 mL of triethylamine (30 mmol) and then,in portions, 20.9 g of MnO₂ (240 mmol). The whole is subsequently heatedat 90° C. for 3 hours. After cooling, the reaction mixture is filteredover a Celite cake and concentrated to dryness. The title product isthen isolated by purification on silica gel (heptane/AcOEt gradient:0-10%) in the form of an oil, which crystallises when cold.

¹H-NMR: δ (300 MHz; dmso-d6; 300° K): 8.5 (d, 1H, H indolizine); 8.05(d, 1H, H indolizine); 7.6 (s, 1H, H indolizine); 7.15 (m, 2H, Hindolizine); 6.85 (m, 1H, H indolizine); 4.25 (q, 2H, —C(O)CH₂CH₃); 1.35(t, 3H, —C(O)CH₂CH₃)

IR: ν: C═O ester: 1675 cm⁻¹; C═C aromatic: 1634 cm⁻¹

Step C:6-[1-(Methoxycarbonyl)-3-indolizinyl]-1,3-benzodioxole-5-carboxylic acid

The procedure is as in the protocol described in Steps C and D ofPreparation 1.

PREPARATION 14 4-Chloro-2-[1-(methoxycarbonyl)-3-indolizinyl]benzoicacid

Methyl 1-indolizinecarboxylate is formed according to the processdescribed in Steps A and B of Preparation 13. The title product issubsequently obtained according to the protocol described in Steps C andD of Preparation 1, replacing the6-bromo-1,3-benzodioxole-5-carbaldehyde used in Step C by2-bromo-4-chlorobenzaldehyde.

PREPARATION 157-[1-(Methoxycarbonyl)-3-indolizinyl]-2,3-dihydro-1,4-benzodioxine-6-carboxylicacid

Methyl 1-indolizinecarboxylate is formed according to the processdescribed in Steps A and B of Preparation 13. The title product issubsequently obtained according to the described in Steps C and D ofPreparation 1, replacing the 6-bromo-1,3-benzodioxole-5-carbaldehydeused in Step C by 7-bromo-2,3-dihydro-1,4-benzodioxine-6-carbaldehyde.

PREPARATION 16 4-Methoxy-2-[1-(methoxycarbonyl)-3-indolizinyl]benzoicacid

Methyl 1-indolizinecarboxylate is formed according to the processdescribed in Steps A and B of Preparation 13. The title product issubsequently obtained according to the protocol described in Steps C andD of Preparation 1, replacing the6-bromo-1,3-benzodioxole-5-carbaldehyde used in Step C by2-bromo-4-methoxybenzaldehyde.

PREPARATION 176-[2-(tert-Butoxycarbonyl)-8-(methoxycarbonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-6-yl]-1,3-benzodioxole-5-carboxylicacid Step A: 1-tert-Butyl 3-methyl 4-formyl-1,3-piperazinedicarboxylate

To a solution of pentafluorophenol in 520 mL of anhydrous ether at 0° C.there are added in succession 49 g of1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (286 mmol) in portionsand 12 mL of formic acid (312 mmol). The whole is stirred at ambienttemperature for 2 hours. There is subsequently added a mixture of 32 gof 1-tert-butyl 3-methyl 1,3-piperazinedicarboxylate (130 mmol) and 18mL of triethylamine (130 mmol) in solution in 520 mL of CH₂Cl₂. Thewhole is stirred overnight at ambient temperature. The reaction mixtureis hydrolysed with an 1N aqueous HCl solution and extracted with CH₂Cl₂.The organic phases are subsequently combined and then washed with asaturated aqueous NaHCO₃ solution and then with a saturated aqueous NaClsolution until neutral. After drying over MgSO₄, filtration andconcentration to dryness, the product is isolated by chromatography oversilica gel (petroleum ether/AcOEt gradient: 0-30%). The title product isobtained in the form of an oil.

IR: ν: C═O: 1674-1745 cm⁻¹

m/z (C₁₂H₂₀N₂O₅): 272.1 (M+); 295.121 (M+Na)⁺; 567.253 (2M+Na)⁺

Step B: Lithium 4-(tert-butoxycarbonyl)-1-formyl-2-piperazinecarboxylate

To a solution of 28 g of the compound obtained in Step A (103 mmol) in515 mL of dioxane there are added 4.8 g of LiOH (113 mmol) in solutionin 100 mL of H₂O. The whole is stirred at ambient temperature for 4hours. The reaction mixture is subsequently concentrated to dryness andthen co-evaporated several times with ethyl acetate. The title productis obtained in the form of a solid and is used directly for thefollowing cyclisation step.

¹³C-NMR: δ (500 MHz; dmso-d6; 300° K): 46 (s, C piperazine); 42-38 (m, Cpiperazine); 58-53 (s, C piperazine); 28.5 (s, C ^(t)Bu).

IR: ν: C═O: 1650 cm⁻¹; 2800 cm⁻¹

Step C: 2-tert-Butyl 8-methyl3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxylate

To a suspension of 29 g of the compound obtained in Step B (103 mmoles)in 800 mL of dichloroethane there are added in succession 24 g of tosylchloride (124 mmol), 12.6 mL of methyl 2-chloroacrylate (124 mmol) andthen 35 mL of triethylamine (247 mmoles). The whole is stirred at refluxfor 2 hours. After cooling, the reaction mixture is diluted with ethylacetate, and the organic phase is washed with a saturated NaCl solutionuntil neutral. After drying over MgSO₄, filtration and concentration todryness, the title product is isolated by chromatography over silica gel(petroleum ether/AcOEt gradient: 0-20%) in the form of a solid.

1H-NMR: δ (400 MHz; dmso-d6; 300° K): 6.8-6.43 (m, 2H, H pyrrole);4.75-3.75 (m, 6H, H piperazine)); 3.73 (s, 3H, H COOCH3); 1.48 (s, 9H, H^(t)Bu).

IR: ν: C═O (conjugated ester): 1712 cm⁻¹; C═O (carbamate): 1677 cm⁻¹

Step D:6-[2-(tert-Butoxycarbonyl)-8-(methoxycarbonyl)-1,2,3,4-tetrahydropyrrolo-[1,2-a]pyrazin-6-yl]-1,3-benzodioxole-5-carboxylicacid

The procedure is as in the protocol described in Steps C and D ofPreparation 1.

PREPARATION 186-[7-(Methoxycarbonyl)-2,3-dihydro-1H-pyrrolizin-5-yl]-1,3-benzodioxole-5-carboxylicacid

The procedure is as in the protocol described in Preparation 1,replacing the 2-piperidinecarboxylic acid used in Step A by proline.

PREPARATION 194-Chloro-2-[7-(methoxycarbonyl)-2,3-dihydro-1H-pyrrolizin-5-yl]-benzoicacid

The procedure is as in the protocol described in Preparation 1,replacing the 2-piperidinecarboxylic acid used in Step A by proline,while the 6-bromo-1,3-benzodioxole-5-carbaldehyde used in Step C isreplaced by 2-bromo-4-chlorobenzaldehyde.

PREPARATION 204-Chloro-2-[8-(methoxycarbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c]-[1,4]oxazin-6-yl]benzoicacid

The procedure is as in the protocol described in Preparation 1,replacing 2-piperidinecarboxylic acid by 3-morpholinecarboxylic acid,while the 6-bromo-1,3-benzodioxole-5-carbaldehyde used in Step C isreplaced by 2-bromo-4-chlorobenzaldehyde.

PREPARATION 216-[8-(Methoxycarbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl]-1,3-benzodioxole-5-carboxylicacid

The procedure is as in the protocol described in Preparation 1,replacing 2-piperidinecarboxylic acid by 3-morpholinecarboxylic acid.

PREPARATION 224-Chloro-2-[1-(methoxycarbonyl)-6,7,8,9-tetrahydro-5H-pyrrolo-[1,2-a]azepin-3-yl]benzoicacid

The procedure is as in the protocol described in Preparation 1,replacing 2-piperidinecarboxylic acid by 2-azepanecarboxylic acid, whilethe 6-bromo-1,3-benzodioxole-5-carbaldehyde used in Step C is replacedby 2-bromo-4-chlorobenzaldehyde.

PREPARATION 236-[1-(Methoxycarbonyl)-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepin-3-yl]-1,3-benzodioxole-5-carboxylicacid

The procedure is as in the protocol described in Preparation 1,replacing 2-piperidinecarboxylic acid by 2-azepanecarboxylic acid.

PREPARATION 244-Chloro-2-[3-(methoxycarbonyl)-5,6,7,8-tetrahydro-1-indolizinyl]-benzoicacid Step A: Methyl 1-(4-bromobutyl)-1H-pyrrole-2-carboxylate

To a suspension of 6.7 g (241.7 mmol) of NaH (60%) in 400 mL ofanhydrous THF at 0° C. there are added 20 g (161.13 mmol) of methyl1H-pyrrole-2-carboxylate (see Tetrahedron 2008, 64, 7745). The whole issubsequently stirred at ambient temperature for one hour. Then, thereare added 95 mL of 1,4-dibromobutane. After the addition, the reactionmixture is heated at reflux for 12 hours. The precipitate obtained isfiltered off and then washed with THF. The filtrate is subsequentlyconcentrated to dryness. The compound is then isolated by chromatographyover silica gel (cyclohexane/ethyl acetate gradient: 0 to 20%) in theform of an oil.

% C % H % N % Br Calculated 46.17 5.42 5.38 30.72 Found 46.76 5.56 5.2930.77

IR: ν: —C═O: 1700 cm⁻¹; ν: C—O—C: 1238 cm⁻¹

Step B: Methyl 5,6,7,8-tetrahydro-3-indolizinecarboxylate

A solution of 8 g (30.8 mmol) of the brominated derivative obtained inStep A in 700 mL of acetonitrile is brought to reflux. There is addedthereto a solution of a mixture of 25 g of azobisisobutyronitrile (151mmol) and of 30 g of Bu₃SnH (100 mmol) in 500 mL of toluene. The wholeis refluxed for 120 hours. The reaction mixture is subsequentlyconcentrated to dryness. The compound is then isolated by chromatographyover silica gel (cyclohexane/ethyl acetate gradient 5 to 10%) in theform of an oil.

¹H-NMR: δ (400 MHz; CDCl₃; 300° K): 6.90 (d, 1H, H pyrrole); 5.85 (d,1H, H pyrrole); 4.30 (t, 2H, CH₂ indolizine); 3.80 (s 3H, Me); 2.80 (t,2H, CH₂ indolizine); 1.95 (m, 2H, CH₂ indolizine); 1.80 (m, 2H, CH₂indolizine)

IR: ν: —C═O: 1695 cm⁻¹

Step C:4-Chloro-2-[3-(methoxycarbonyl)-5,6,7,8-tetrahydro-1-indolizinyl]benzoicacid

The procedure is as in the protocol described in Steps C and D ofPreparation 1.

PREPARATION 252-[1-(Methoxycarbonyl)-5,6,7,8-tetrahydroindolizin-3-yl]-4-methyl-benzoicacid

The procedure is as in the process of Preparation 1, replacing the6-bromo-1,3-benzodioxole-5-carbaldehyde used in Step C by2-bromo-4-methylbenzaldehyde.

PREPARATION 264-Fluoro-2-[8-(ethoxycarbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]-oxazin-6-yl]benzoicacid

The procedure is as in the protocol described in Preparation 1,replacing 2-piperidinecarboxylic acid by 3-morpholinecarboxylic acid,while the 6-bromo-1,3-benzodioxole-5-carbaldehyde used in Step C isreplaced by 2-bromo-4-fluorobenzaldehyde.

PREPARATION 274-Fluoro-2-[1′-(methoxycarbonyl)-5′,6′-dihydro-8′H-spiro[1,3-dioxolane-2,7′-indolizin]-3′-yl]benzoicacid Step A: Methyl8-formyl-1,4-dioxa-8-azaspiro[4.5]decane-7-carboxylate

24 g of methyl 1,4-dioxa-8-azaspiro[4.5]decane-9-carboxylate (111 mmol)are dissolved in 80 mL of ethyl acetate and 80 mL of dichloromethane.There are added 26 g of (4-nitrophenyl) formate (155 mmol), and thewhole is stirred at ambient temperature for one hour. The reactionmixture is evaporated to dryness and taken up in ethyl acetate. Theorganic phase is subsequently washed in succession with a 1 N NaOHsolution, water, and then with a saturated NH₄Cl solution until aneutral pH is reached. It is subsequently dried over magnesium sulphate,filtered and concentrated to dryness. The oil so obtained is purified byflash chromatography (heptane/ethyl acetate gradient). The title productis obtained in the form of an oil.

¹H-NMR: δ (400 MHz; dmso-d6; 300° K): 8.15 (s, 1H, CHO); 5.0-4.75 (m,1H, H tertiary); 4.3-3.7 (m, 5H, 4H ethylenedioxy+1H aliphaticpiperidine); 3.70 (s, 3H, Me); 3.4-2.9 (2m, 1H, H aliphatic piperidine);2.3-1.75 (m, 2H, H aliphatic piperidine); 1.7-1.5 (m, 2H, H aliphaticpiperidine)

Step B: 8-Formyl-1,4-dioxa-8-azaspiro[4.5]decane-7-carboxylic acid

15.25 g of the compound obtained in Step A (62.7 mmol) are dissolved in160 ml of dioxane. A solution of 125 mL of 1M KOH is added dropwise, andthe whole is stirred at ambient temperature for one hour. There aresubsequently added 125 mL of 1M HCl, and the compound is extracted withdichloromethane. The organic phase is dried over MgSO₄, filtered andconcentrated to dryness. The title product is obtained in the form of apowder.

¹H-NMR: δ (400 MHz; dmso-d6; 300° K) 13.5-12 (m, 1H, OH); 8.1+8.0 (2s,1H, CHO); 4.9+4.6 (2m, 1H, H tertiary); 4.0-3.8 (m, 4H, ethylenedioxy);4.2+3.7 (2 ms, 1H, H aliphatic piperidine); 3.4+2.9 (2m, 1H, H aliphaticpiperidine); 2.4-1.5 (m, 4H, H aliphatic piperidine)

IR: ν: OH: 3500-2000 cm⁻¹; —C═O (acid+aldehyde): 1731+1655 cm⁻¹

Step C: Methyl5′,6′-dihydro-8′H-spiro[1,3-dioxolane-2,7′-indolizine]-1′-carboxylate

To a solution of 13.5 g (62.7 mmol) of the acid obtained in Step B in380 mL of dichloroethane there are added in succession 39.5 mL (238.4mmol) of triethylamine and then, by spatula, 12.5 g (65.6 mmol) ofpara-toluenesulphonyl chloride and 23.7 mL (238.4 mmol) of methylchloroacrylate. The whole is stirred at 80° C. for 18 hours. Thereaction mixture is subsequently filtered over Celite. The filtrate issubsequently washed with a saturated NaHCO₃ solution and then with asaturated NH₄Cl solution. The organic phase is dried over MgSO₄,filtered and concentrated to dryness. The oil so obtained is purified byflash chromatography (heptane/ethyl acetate gradient). The product isobtained in the form of a solid.

¹H-NMR: δ (400 MHz; dmso-d6; 300° K) 6.70 (d, 1H, pyrrole); 6.40 (d, 1H,pyrrole); 4.05 (t, 2H, H aliphatic, piperidine); 4.00 (m, 4H,ethylenedioxy); 3.70 (s, 3H, methyl); 3.15 (s, 2H, H aliphaticpiperidine); 2.05 (t, 2H, H aliphatic piperidine)

IR: ν: —C═O (ester): 1689 cm⁻¹

Step D: Methyl3′-(5-fluoro-2-formylphenyl)-5′,6′-dihydro-8′H-spiro[1,3-dioxolane-2,7′-indolizine]-1′-carboxylate

The procedure is as in the process of Step C of Preparation 1, replacing6-bromo-1,3-benzodioxole-5-carbaldehyde by 2-bromo-4-fluorobenzaldehyde.

Step E:4-Fluoro-2-[1′-(methoxycarbonyl)-5′,6′-dihydro-8′H-spiro[1,3-dioxolane-2,7′-indolizin]-3′-yl]benzoicacid

The procedure is as in the process of Step D of Preparation 1.

PREPARATION 284-Fluoro-2-[(2R)-2-hydroxy-7-(methoxycarbonyl)-2,3-dihydro-1H-pyrrolizin-5-yl]benzoicacid Step A: Methyl(4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-L-prolinate

The protection of the alcohol function ofmethyl(4R)-4-hydroxy-L-prolinate by a tert-butyldimethylsilyl group iscarried out according to the protocol described in document

Step B:Methyl(4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-formyl-L-prolinate

13.7 g (52.8 mmol) of compound of Step A are dissolved in 100 mL ofacetonitrile. There are added thereto 13.2 g (79.3 mmol) of(4-nitrophenyl) formate and 39 mL (238 mmol) of diisopropylethylamine.The whole is stirred at ambient temperature for 6 hours. The reactionmixture is evaporated to dryness and taken up in ethyl acetate. Theorganic phase is subsequently washed in succession with a 1 N NaOHsolution, with water, and then with a saturated NH₄Cl solution untilneutral. It is subsequently dried over magnesium sulphate, filtered andconcentrated to dryness. The oil so obtained is purified by flashchromatography (gradient: dichloromethane/ammoniacal methanol). Thetitle product is obtained in the form of an oil.

¹H-NMR: δ (400 MHz; dmso-d6; 300° K): 8.15 and 8.12 (s, 1H, formyl);4.62 and 4.25 (t, 1H, H alpha ester); 4.40 (m, 1H, SiOCH,); 3.65 and 3.6(s, 3H, OMe); 3.5 and 3.3 (m, 2H, 2H proline); 2.12 and 1.95 (m, 2H, 2Hproline); 0.8 (s, 9H, Si^(t)Bu); 0.05 (s, 6H, SiMe₂).

IR: ν: C═O ester: 1749 cm⁻¹; C═O formyl: 1659 cm⁻¹

Step C: Lithium(2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-formylpyrrolidine-2-carboxylate

The compound of Step B (26.2 g; 91.1 mmol) is dissolved in 450 mL ofdioxane. A solution of lithium hydroxide (4.2 g; 100 mmol) in water (90mL) is added. The whole is stirred at ambient temperature for 7 hours.The reaction mixture is evaporated to dryness and used as such for thefollowing step.

Step D:Methyl(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2,3-dihydro-1H-pyrrolizine-7-carboxylate

To a solution of 22.4 g (80.2 mmol) of the lithium carboxylate obtainedin Step D in 640 mL of dichloroethane there are added in succession 27mL (192 mmol) of triethylamine and then, in portions, 18 g (96 mmol) ofpara-toluenesulphonic chloride and 9.7 mL (96.2 mmol) of methylchloroacrylate. The reaction mixture is heated at reflux for 18 hoursand then cooled and diluted in ethyl acetate. The organic phase iswashed with water and then with brine, before being dried over MgSO₄.After filtration and concentration of the mixture, the oil obtained ispurified by flash chromatography (gradient: heptane/ethyl acetate). Thetitle product is obtained in the form of an oil.

¹H-NMR: δ (400 MHz; dmso-d6; 300° K): 6.7 (d, 1H, H pyrrole); 6.4 (d,1H, H pyrrole); 5.0 (m, 1H, SiOCH,); 4.2-3.75 (ABx, 2H, 2Hdihydropyrrolizine); 3.3+2.8 (ABx, 2H, 2H dihydropyrrolizine); 3.70 (s,3H, CO₂CH₃); 0.9 (s, 9H, ^(t)Bu); 0.10 (ABx, 6H, SiMe₂)

IR: ν: —C═O (ester): 1701 cm⁻¹; SiCH₃: 1249 cm⁻¹; Si—O: 1118-1090 cm⁻¹;Si—C: 835-777 cm⁻¹

Step E:Methyl(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-5-(5-fluoro-2-formylphenyl)-2,3-dihydro-1H-pyrrolizine-7-carboxylate

The procedure is as in the process of Step C of Preparation 1, replacing6-bromo-1,3-benzodioxole-5-carbaldehyde by 2-bromo-4-fluorobenzaldehyde.

Step F:2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-7-(methoxycarbonyl)-2,3-dihydro-M-pyrrolizin-5-yl]-4-fluorobenzoicacid

The procedure is as in the process of Step D of Preparation 1.

PREPARATION 294-Fluoro-2-[(2S)-2-hydroxy-7-(methoxycarbonyl)-2,3-dihydro-1H-pyrrolizin-5-yl]benzoicacid

The procedure is as in the process of Preparation 28, replacing themethyl(4R)-4-hydroxy-L-prolinate used in Step A bymethyl(4S)-4-hydroxy-L-prolinate.

PREPARATION 304-Fluoro-2-[7-hydroxy-1-(methoxycarbonyl)-5,6,7,8-tetrahydroindolizin-3-yl]benzoicacid

The procedure is as in the process of Preparation 27, replacing the2-bromo-4-fluorobenzaldehyde used in Step D by6-bromo-1,3-benzodioxole-5-carbaldehyde.

PREPARATION 316-[8-(Methoxycarbonyl)pyrrolo[1,2-a]pyrazin-6-yl]-1,3-benzodioxole-5-carboxylicacid Step A: Methyl pyrrolo[1,2-a]pyrazine-8-carboxylate

To a solution of 10 g (65.7 mmol) of methyl pyrazin-2-ylacetate in 263mL of anhydrous acetone (4 mL/mmol) there are added in succession 5.7 gof lithium bromide (65.7 mmol), 22.1 g of sodium bicarbonate (263 mmol)and then 9.4 mL of chloroacetaldehyde (50% solution in water) (72.6mmoles). The whole is subsequently heated at reflux overnight. Thereaction mixture is subsequently concentrated to dryness and then takenup in ethyl acetate. The organic phase is washed with a saturated sodiumchloride solution, dried over magnesium sulphate, filtered and thenconcentrated to dryness. There is obtained an oil, which is purified bychromatography over silica gel (CH₂Cl₂/ethyl acetate gradient). Afterconcentration, the title product is obtained in the form of a solid.

¹H-NMR: δ (400 MHz; dmso-d6; 300° K): 9.36 (m, 1H, H pyrazine); 8.50(dd, 1H, H pyrazine)); 7.8 (m, 2H, 1H pyrazine, 1H pyrrole); 7.31 (m,1H, H pyrrole). 3.88 (s, 3H, OCH₃)

IR: ν: —C═O (conjugated ester): 1686 cm⁻¹

Step B:6-[8-(Methoxycarbonyl)pyrrolo[1,2-a]pyrazin-6-yl]-1,3-benzodioxole-5-carboxylicacid

The procedure is as in the processes of Steps C and D of Preparation 1.

PREPARATION 32 4-Fluoro-2-[1-(methoxycarbonyl)-3-indolizinyl]benzoicacid

Methyl 1-indolizinecarboxylate is formed according to the processdescribed in Steps A and B of Preparation 13. The title product issubsequently obtained according to the protocol described in Steps C andD of Preparation 1, replacing the6-bromo-1,3-benzodioxole-5-carbaldehyde used in Step C by2-bromo-4-fluorobenzaldehyde.

PREPARATION 1′(3S)-3-(4-Morpholinylmethyl)-1,2,3,4-tetrahydroisoquinoline Step A:Benzyl(3S)-3-(4-morpholinylcarbonyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate

To a solution of 5 g of(3S)-2-[(benzyloxy)carbonyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid (16 mmol) in 160 mL of dichloromethane there are added 1.5 mL ofmorpholine (17.6 mmol) and then 9 mL of N,N,N-triethylamine (64 mmol),3.3 g of 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (EDC) (19.2mmol) and 2.6 g of hydroxybenzotriazole (HOBT) (19.2 mmol). The reactionmixture is stirred at ambient temperature overnight and is then pouredonto a solution of ammonium chloride and extracted with ethyl acetate.The organic phase is subsequently dried over magnesium sulphate and thenfiltered and evaporated to dryness. The crude product so obtained isthen purified by chromatography over silica gel(dichloromethane/methanol gradient). The product is obtained in the formof a foam.

¹H-NMR: δ (400 MHz; dmso-d6; 353° K): 7.30 (m, 5H benzyl); 7.15 (m, 4Haromatic); 5.2-5.0 (m, 3H, 2H benzyl, 1H dihydroisoquinoline); 4.75-4.5(2d, 2H dihydroisoquinoline); 3.55-3.3 (m, 8H morpholine); 3.15-2.9(2dd, 2H dihydroisoquinoline)

IR: ν: >C═O: 1694; 1650 cm⁻¹

Step B:Benzyl(3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate

To a solution of 5.3 g of the product obtained in Step A (13.9 mmol) in278 mL of tetrahydrofuran there are added 14 mL of BH₃Me₂S (27.8 mmol)at ambient temperature. The whole is heated for 4 hours at 80° C. It isallowed to return to ambient temperature, and then there are added 7 mL(14 mmol) of BH₃Me₂S. The reaction mixture is again heated at 80° C. for2 hours. The tetrahydrofuran is subsequently evaporated off, and thereare then added slowly methanol and then 5.6 mL of 5N hydrochloric acid(27.8 mmol). The mixture is stirred at ambient temperature overnight andthen at 80° C. for one hour. There is subsequently added a saturatedNaHCO₃ solution to the reaction mixture at 0° C. until a pH of 8 isreached, and then extraction with ethyl acetate is carried out. Theorganic phase is subsequently dried over magnesium sulphate and thenfiltered and evaporated to dryness. The title product is obtained in theform of an oil.

¹H-NMR: δ (400 MHz; dmso-d6; 353° K): 7.43-7.30 (unresolved peak, 5Hbenzyl); 7.19 (m, 4H aromatic); 5.16 (m, 2H, 2H benzyl); 4.79-4.29 (d,2H dihydroisoquinoline); 4.58 (m, 1H dihydroisoquinoline); 3.50 (m, 4Hmorpholine); 3.02-2.80 (dd, 2H dihydroisoquinoline); 2.42-2.28(unresolved peak, 5H, 4H morpholine, 1H morpholine); 2.15 (dd, 1Hmorpholine)

IR: ν: >CH: 2810 cm⁻¹; ν: >C═O: 1694 cm⁻¹; ν: >C—O—C<: 1114 cm⁻¹;ν: >CH—Ar: 751; 697 cm⁻¹

Step C: (3S)-3-(4-Morpholinylmethyl)-1,2,3,4-tetrahydroisoquinoline

To a solution of 4.9 g of the compound of Step B (13.4 mmol) in 67 mL ofethanol there is added 0.980 g of palladium dihydroxide (20% by mass) atambient temperature. The reaction mixture is placed under 1.2 bar ofhydrogen at ambient temperature for 4 hours. It is subsequently passedover a Whatman filter, and then the palladium is rinsed several timeswith ethanol. The filtrate is evaporated to dryness. The title productis obtained in the form of an oil.

¹H-NMR: δ (400 MHz; dmso-d6; 300° K): 7.12-7.0 (unresolved peak, 4Haromatic); 3.92 (s, 2H tetrahydroisoquinoline); 3.60 (t, 4H morpholine);2.98 (m, 1H tetrahydroisoquinoline); 2.68 (dd, 1Htetrahydroisoquinoline); 2.5-2.3 (unresolved peak, 8H, 1Htetrahydroisoquinoline, 6H morpholine, 1H NH)

IR: ν: >NH: 3322 cm⁻¹; ν: >C—O—C<: 1115 cm⁻¹; ν: >CH—Ar: 742 cm⁻¹

PREPARATION 2′ 3R-3-(4-Morpholinylmethyl)-1,2,3,4-tetrahydroisoquinoline

The procedure is as in the process of Preparation 1′, replacing the(3S)-2-[(benzyloxy)carbonyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid used in Step A by(3R)-2-[(benzyloxy)carbonyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid.

PREPARATION 3′(3.5)-3-[(4-Methyl-1-piperazinyl)methyl]-1,2,3,4-tetrahydroisoquinoline

The procedure is as in the process of Preparation 1′, replacing themorpholine used in Step A by 1-methyl-piperazine.

PREPARATION 4′(3S)-3-(1,4-Oxazepan-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline

The procedure is as in the process of Preparation 1′, replacing themorpholine used in Step A by 1,4-oxazepan.

PREPARATION 5′(3S)-3-{[(3R)-3-Methylmorpholinyl]methyl}-1,2,3,4-tetrahydroisoquinoline

The procedure is as in the process of Preparation 1′, replacing themorpholine used in Step A by (3R)-3-methylmorpholine.

PREPARATION 6′(3S)-3-{[(3S)-3-Methylmorpholinyl]methyl}-1,2,3,4-tetrahydroisoquinoline

The procedure is as in the process of Preparation 1′, replacing themorpholine used in Step A by (3S)-3-methylmorpholine.

PREPARATION 7′(3S)-3-{[(3S,5S)-3,5-Dimethylmorpholinyl]methyl}-1,2,3,4-tetrahydroisoquinoline

The procedure is as in the process of Preparation 1′, replacing themorpholine used in Step A by (3S,5S)-3,5-dimethylmorpholine.

PREPARATION 8′N,N-Dimethyl[(3S)-1,2,3,4-tetrahydro-3-isoquinolinyl]methanamine

The procedure is as in the process of Preparation 1′, replacing themorpholine used in Step A by N,N-dimethylamine.

PREPARATION 9′(3S)-3-{[4-(2-Methoxyethyl)piperazin-1-yl]methyl}-1,2,3,4-tetrahydroisoquinoline

The procedure is as in the process of Preparation 1′, replacing themorpholine used in Step A by 1-(2-methoxyethyl)piperazine.

PREPARATION 10′1-Methyl-4-[(3S)-1,2,3,4-tetrahydroisoquinolin-3-ylmethyl]-piperazin-2-one

The procedure is as in the process of Preparation 1′, replacing themorpholine used in Step A by 1-methylpiperazin-2-one.

PREPARATION 11′2-Methoxy-N-methyl-N-[(3S)-1,2,3,4-tetrahydroisoquinolin-3-yl-methyl]ethanamine

The procedure is as in the process of Preparation 1′, replacing themorpholine used in Step A by 2-methoxy-N-methylethanamine.

PREPARATION 12′N-Ethyl-2-methoxy-N-[(3S)-1,2,3,4-tetrahydroisoquinolin-3-yl-methyl]ethanamine

The procedure is as in the process of Preparation 1′, replacing themorpholine used in Step A by N-ethyl-2-methoxyethanamine.

PREPARATION 13′(3S)-3-{[4-(Methylsulphonyl)piperazin-1-yl]methyl}-1,2,3,4-tetrahydroisoquinoline

The procedure is as in the process of Preparation 1′, replacing themorpholine used in Step A by 1-(methylsulphonyl)piperazine.

PREPARATION 14′(3S)-3-{[4-(2,2,2-Trifluoroethyl)piperazin-1-yl]methyl}-1,2,3,4-tetrahydroisoquinoline

The procedure is as in the process of Preparation 1′, replacing themorpholine used in Step A by 1-(2,2,2-trifluoroethyl)piperazine.

PREPARATION 15′(3S)-3-[(1,1-dioxidothiomorpholin-4-yl)methyl]-1,2,3,4-tetrahydroisoquinoline

The procedure is as in the process of Preparation 1′, replacing themorpholine used in Step A by thiomorpholine 1,1-dioxide.

PREPARATION 16′(3S)-3-[(3-Methoxypyrrolidin-1-yl)methyl]-1,2,3,4-tetrahydroisoquinoline

The procedure is as in the process of Preparation 1′, replacing themorpholine used in Step A by 3-methoxypyrrolidine.

PREPARATION 17′(3S)-3-[(3,3-Difluoropyrrolidin-1-yl)methyl]-1,2,3,4-tetrahydroisoquinoline

The procedure is as in the process of Preparation 1′, replacing themorpholine used in Step A by 3,3-difluoropyrrolidine.

PREPARATION 18′(3S)-3-[(3-methoxyazetidin-1-yl)methyl]-1,2,3,4-tetrahydroisoquinoline

The procedure is as in the process of Preparation 1′, replacing themorpholine used in Step A by 3-methoxyazetidine.

PREPARATION 19′(3S)-3-[(3-fluoroazetidin-1-yl)methyl]-1,2,3,4-tetrahydroisoquinoline

The procedure is as in the process of Preparation 1′, replacing themorpholine used in Step A by 3-fluoroazetidine.

PREPARATION 1″ 4-{[tert-Butyl(dimethyl)silyl]oxy}-N-phenylaniline

To a solution of 12 g of 4-anilinophenol (64.7 mmol) in 200 mL ofacetonitrile there are added at ambient temperature 6.7 g of imidazole(97.05 mmol) and 11.7 g of tert-butyl(chloro)dimethylsilane (77.64mmol). The whole is stirred at 70° C. for 4 hours. Then the reactionmixture is poured onto water and extracted with ether. The organic phaseis subsequently dried over magnesium sulphate and then filtered andevaporated to dryness. The crude product so obtained is then purified bychromatography over silica gel (petroleum ether/dichloromethanegradient). The title product is obtained in the form of a powder.

¹H-NMR: δ (400 MHz; dmso-d6; 300° K): 7.84 (s, 1H NH); 7.17 (t, 2Haniline); 6.98 (d, 2H phenoxy); 6.94 (d, 2H aniline); 6.76 (d, 2Hphenoxy); 6.72 (t, 1H aniline); 0.95 (s, 9H tert-butyl); 0.15 (s, 6Hdimethyl)

IR: ν: >NH: 3403 cm⁻¹; >Ar: 1597 cm⁻¹

The amines NHR₃R₄ wherein R₃ and R₄ independently of one anotherrepresent an aryl or heteroaryl group are prepared according to knownprocedures described in the literature (Surry D. S et al., ChemicalScience, 2011, 2, 27-50, Charles M. D. et al., Organic Letters, 2005, 7,3965-3968). The reaction of protection of the hydroxy function of the4-anilinophenol described in Preparation 1″ can be applied to varioussecondary amines NHR₃R₄ (as defined hereinbefore) having one or morehydroxy functions, when they are available commercially. Alternatively,the secondary amines having at least one hydroxy substituent may besynthesised directly in a protected form, i.e. starting from reagentswhose hydroxy function has been protected beforehand. Among theprotecting groups, tert-butylsilyloxy and benzyloxy are especiallypreferred.

Among the amines NHR₃R₄ having a hydroxy substituent that are used forsynthesising the compounds of the invention there may be mentioned:4-(4-toluidino)phenol, 4-(4-chloroanilino)phenol,4-(3-fluoro-4-methylanilino)phenol,4-[4-(trifluoromethoxy)anilino]-phenol, 4-[4-hydroxyanilino]phenol,{4-[(1-methyl-1H-indol-6-yl)amino]phenyl}-methanol,4-(2,3-dihydro-1H-indol-6-ylamino)phenol,4-[(1-methyl-2,3-dihydro-1H-indol-6-yl)amino]phenol,4-[(1-methyl-1H-indol-6-yl)amino]phenol,4-[(1-methyl-1H-indol-6-yl)amino]cyclohexanol,4-[(1-methyl-1,2,3,4-tetrahydro-6-quinolinyl)amino]phenol,4-[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)amino]phenol,4-[4-(diethylamino)anilino]-phenol,4-(2,3-dihydro-1H-inden-5-ylamino)phenol,4-[(1-methyl-1H-indazol-5-yl)amino]-phenol,4-[(1′-methyl-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-5′-yl)amino]phenol,4-[(1,3,3-trimethyl-2,3-dihydro-1H-indol-5-yl)amino]phenol,4-[4-methoxy-3-(trifluoro-methyl)anilino]phenol,4-[4-(methylsulphanyl)-3-(trifluoromethyl)anilino]phenol,2-fluoro-4-[(1-methyl-1H-indol-5-yl)amino]phenol,4-[(1-ethyl-1H-indol-5-yl)amino]phenol,4-[(1-ethyl-2,3-dihydro-1H-indol-5-yl)amino]phenol,4-[(1-isopropyl-2,3-dihydro-1H-indol-5-yl)amino]phenol,4-(butylamino)phenol, 3-[(1-methyl-1H-indol-5-yl)amino]-1-propanol,4-[(1-methyl-1H-indol-5-yl)amino]-1-butanol,4-[(3-fluoro-4-methylphenyl)-amino]phenol,4-[(3-chloro-4-methylphenyl)amino]phenol,4-[(4-fluorophenyl)amino]-phenol,4-[(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)amino]phenol,4-[(4-fluorophenyl)-amino]phenol, 4-[(2-fluorophenyl)amino]phenol,4-[(3-fluorophenyl)amino]phenol, 4-[(2,4-difluorophenyl)amino]phenol,4-[(3,4-difluorophenyl)amino]phenol,3-[(4-hydroxyphenyl)amino]benzonitrile,4-[(3-methoxyphenyl)amino]phenol, 4-[(3,5-difluorophenyl)-amino]phenol,4-[(3-methylphenyl)amino]phenol, 4-[(4-hydroxyphenyl)amino]benzonitrile,4-[(3-chlorophenyl)amino]phenol, 4-(pyrimidin-2-ylamino)phenol,4-[(cyclobutylmethyl)amino]phenol,2-[(4-hydroxyphenyl)amino]benzonitrile,4-{[(1-methyl-1H-pyrazol-4-yl)methyl]amino}phenol,4-[(cyclopropylmethyl)amino]phenol,4-{[(1-methyl-1H-pyrazol-3-yl)methyl]amino}phenol,4-(but-2-yn-1-ylamino)phenol, 4-(pyrazin-2-yl-amino)phenol,4-(pyridin-2-ylamino)phenol, 4-(pyridazin-3-ylamino)phenol,4-(pyrimidin-5-ylamino)phenol, 4-(pyridin-3-ylamino)phenol,4-[(3,5-difluoro-4-methoxyphenyl)-amino]phenol,4-(pyridin-4-ylamino)phenol, 4-[(3-fluoro-4-methoxyphenyl)amino]phenol,2-(phenylamino)pyrimidin-5-ol, 5-[(4-hydroxyphenyl)amino]-2-methoxybenzonitrile, 4-{[3-(trifluoromethyl)phenyl]amino}phenol.

The hydroxy function(s) of the secondary amines listed above is (are)protected beforehand by a suitable protecting group prior to coupling toan acid derivative of the compound of formula (VII) as defined in thepreceding general process.

EXAMPLE 1N-(4-Hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-N-phenyl-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride Step A: Methyl3-{6-[((3S)-3-(4-Morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxylate

To a solution of 2 g of the compound of Preparation 1 in 20 mL ofdichloromethane there are added at ambient temperature 5.5 mL ofN,N,N-triethylamine (6.96 mmol), 2.12 g of the compound of Preparation1′ (6.96 mmol), and then 0.94 g of hydroxybenzotriazole (HOBT) and 1.34g of 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (EDC) (6.96 mmol).The reaction mixture is subsequently stirred at ambient temperatureovernight, and is then poured onto an ammonium chloride solution andextracted with ethyl acetate. The organic phase is subsequently driedover magnesium sulphate and then filtered and evaporated to dryness. Thecrude product so obtained is then purified by chromatography over silicagel (heptane/AcOEt gradient). The title product is obtained in the formof an oil.

¹H-NMR: δ (500 MHz; dmso-d6; 300° K): 7.2-6.9 (m, 4H, H aromatic);7.04-7.03-7.00 (m, 1H, H aromatic); 6.85 (m, 1H, H aromatic);6.35-6.26-6.06 (m, 1H, H tetrahydroindolizine); 6.15-6.12 (m, 2H, Hmethylenedioxy); 5.06-4.84 (m, 1H, H dihydroisoquinoline); 4.86-4.17 (m,2H, H dihydroisoquinoline); 3.65-3.6-3.55 (m, 3H, H methyl ester);3.43-4.26 (m, 2H, H tetrahydroindolizine); 3.58-3.5 (m, 4H, Hmorpholine); 2.37-3.05 (m, 4H, 2H dihydroisoquinoline, 2Htetrahydroindolizine); 1.68-2.56 (m, 4H, H morpholine); 1.4-2.0 (m, 4H,H tetrahydroindolizine)

IR: ν: >C═O 1695 cm⁻¹ ester; ν: >C═O 1625 cm⁻¹ amide;ν: >C—O—C<1214-1176-1115 cm⁻¹; >CH—Ar 772-744 cm⁻¹

Step B: Lithium3-[6-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,3-benzodioxol-5-yl]-5,6,7,8-tetrahydro-1-indolizinecarboxylate

To a solution of 4.6 g of the compound of Step A (8.26 mmol) in 24 mL ofdioxane there is added a solution of lithium hydroxide (675 mg, 16.1mmol). The whole is placed in a 140 W microwave oven at 100° C. for aperiod of 2.5 hours. The reaction mixture is subsequently filtered anddried. The solid so obtained is dried at 40° C. in a hot cabinet in thepresence of P₂O₅.

¹H-NMR: δ (400 MHz; dmso-d6; 353° K): 6.7-7.15 (unresolved peak, 6H, Haromatic);

6.21 (s, 1H, H aromatic); 6.03 (s, 2H,H methylenedioxy); 4.0-5.0(unresolved peak, 3H dihydroisoquinoline); 3.4-3.6 (unresolved peak, 3Htetrahydroindolizine, 3H morpholine); 2.5-3.1 (unresolved peak, 4H, 2Htetrahydroindolizine, 2H morpholine); 1.5-2.4 (unresolved peak, 10Hmorpholine)

IR: ν: >C═O 1567 broad cm⁻¹ acetate; ν: 1236 cm⁻¹

Step C:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-N-phenyl-5,6,7,8-tetrahydro-1-indolizinecarboxamide

To a solution of 2.6 g of the compound of Step B (4.73 mmol) in 47 mL ofdichloromethane there are added, dropwise, 1.2 mL of oxalyl chloride at0° C. The reaction mixture is stirred at ambient temperature for 11hours, and then co-evaporated several times with dichloromethane. Theproduct so obtained is suspended in 37 mL of dichloromethane and is thenadded to a solution of 2.1 g of the compound obtained in Preparation 1″(7.1 mmol) in 10 mL of dichloromethane in the presence of 0.6 mL ofpyridine (7.1 mmol). The whole is stirred at ambient temperatureovernight. The reaction mixture is concentrated and purified bychromatography over silica gel (dichloromethane/methanol gradient). Thetitle product is obtained in the form of a foam.

¹H-NMR: δ (500 MHz; dmso-d6; 300° K): 6.9-7.3 (9H aromatic); 6.88 (2Haromatic); 6.72-6.87 (2H aromatic); 6.64 (2H aromatic); 6.13 (2Hmethylenedioxy); 5.05-4.74 (1H dihydroisoquinoline); 4.25-4.13 (2Hdihydroisoquinoline); 3.44-3.7 (4H morpholine); 3.62-3.52 (2Htetrahydroindolizine); 3.0-2.6 (4H, 2H tetrahydroindolizine, 2Hdihydroisoquinoline); 2.54-1.94 (6H morpholine); 1.91-1.53 (4Htetrahydroindolizine); 0.92 (9H tert-butyl); 0.17 (6H dimethyl)

IR: ν: >C═O: 1632 cm⁻¹; ν: >C—O—C<: 1237 cm⁻¹; ν: —Si—O—C—: 1035 cm⁻¹;—Si—C—: 910 cm⁻¹; >CH—Ar: 806 cm⁻¹

Step D:N-(4-Hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-N-phenyl-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

To a solution of 1.9 g of the compound obtained in Step C (2.3 mmol) in4 mL of methanol there is added 0.646 g (11.5 mmol) of potassiumhydroxide dissolved in 8 mL of methanol. The whole is stirred at ambienttemperature for 30 minutes. The reaction mixture is subsequently dilutedin dichloromethane and washed in succession with a 1N HCl solution, asaturated NaHCO₃ solution and then a saturated NaCl solution until aneutral pH is reached. The organic phase is subsequently dried overmagnesium sulphate, filtered and evaporated. The crude product soobtained is purified on silica gel (dichloromethane/methanol gradient).The solid is subsequently dissolved in dichloromethane, and 2 mL of 1Nethereal hydrogen chloride are added. The whole is stirred for one hourand then evaporated to dryness. The hydrochloride so obtained isdissolved in a water/acetonitrile mixture until completely dissolved andis then lyophilised.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 69.11 5.8 7.5 4.74 Found 68.95 5.46 7.514.48

Rotatory power: (α)_(D) ²⁰=+50.8° (c=9 mg/mL, MeOH)

EXAMPLE 2N-(4-Hydroxyphenyl)-N-(4-methylphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1″ used in Step C by4-{[tert-butyl(dimethyl)silyl]oxy}-N-(4-methylphenyl)aniline.

Elemental microanalysis:

% C % H % N % Cl % Cl⁻ Calculated 69.42 5.96 7.36 4.66 4.66 Found 69.195.76 7.19 4.62 4.48

EXAMPLE 3N-(4-Chlorophenyl)-N-(4-hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1″ used in Step C by4-{[tert-butyl(dimethyl)silyl]oxy}-N-(4-chlorophenyl)aniline.

Elemental microanalysis:

% C % H % N % Cl % Cl⁻ Calculated 66.07 5.42 7.17 9.07 4.54 Found 65.745.14 7.08 9.02 4.48

Rotatory power: (α)_(D) ²⁰=+80.9° (c=2.5 mg/mL, MeOH)

EXAMPLE 4N-(3-Fluoro-4-methylphenyl)-N-(4-hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1″ used in Step C by4-{[tert-butyl(dimethyl)silyl]oxy}-N-(3-fluoro-4-methylphenyl)aniline.

High-resolution mass (ESI+):

C₄₄H₄₃FN₄O₆  Empirical formula:

[M+H]⁺ calculated: 743.3245

[M+H]⁺ measured: 743.3250

Rotatory power: (α)_(D) ²⁰=+40.7° (c=2.5 mg/mL, MeOH)

EXAMPLE 5N-(4-Hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-N-[4-(trifluoromethoxy)phenyl]-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1″ used in Step C by4-{[tert-butyl(dimethyl)silyl]oxy}-N-(4-trifluoromethoxyphenyl)aniline.

Elemental microanalysis:

% C % H % N % Cl− Calculated 63.57 5.09 6.74 4.26 Found 63.38 4.95 6.884.23

EXAMPLE 6N,N-bis(4-Hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydra-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1″ used in Step C by4-{[tert-butyl(dimethyl)silyl]oxy}-N-(4-{[tert-butyl(dimethyl)silyl]-oxy}phenyl)aniline.

Elemental microanalysis:

% C % H % N % Cl− Calculated 67.66 5.68 7.34 4.64 Found 67.11 5.49 7.314.74

Rotatory power: (α)_(D) ²⁰=+50.8° (c=6 mg/mL, MeOH)

EXAMPLE 7N-[4-(Hydroxymethyl)phenyl]-N-(1-methyl-1H-indol-5-yl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1″ used in Step C byN-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 69.32 5.94 8.6 4.35 Found 69.63 5.75 8.594.13

EXAMPLE 8N-(2,3-Dihydro-1H-indol-5-yl)-N-[4-(hydroxy)phenyl]-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide bis(hydrochloride)

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1″ used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-5-indolinamine.

Elemental microanalysis:

% C % H % N % Cl Calculated 65.53 5.74 8.49 8.60 Found 65.47 5.69 8.437.82

Rotatory power: (α)_(D) ²⁰=+40.9° (c=3.5 mg/mL, MeOH)

EXAMPLE 9N-[4-(Hydroxy)phenyl]-N-(1-methyl-2,3-dihydro-1H-indol-5-yl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1″ used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-5-indolinamine.

High-resolution mass (ESI+):

C₄₆H₄₇N₅O₆  Empirical formula:

[M+H]⁺ calculated: 766.3605

[M+H]⁺ measured: 766.3601

EXAMPLE 10N-[4-(Hydroxy)phenyl]-N-(1-methyl-1H-indol-5-yl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1″ used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis: (theory for 1.1 HCl)

% C % H % N % Cl⁻ Calculated 68.72 5.78 8.71 4.85 Found 68.39 5.55 8.664.33

Rotatory power: (α)_(D) ²⁰=+37.6° (c=7 mg/mL, MeOH)

EXAMPLE 11N-(4-Hydroxyphenyl)-3-{6-[((3R)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-N-phenyl-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1′ used in Step A by the compound of Preparation 2′.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 69.11 5.80 7.50 4.74 Found 68.89 5.23 7.414.62

Rotatory power: (α)_(D) ²⁰=−45.1° (c=9 mg/mL, MeOH)

EXAMPLE 12N-(4-Hydroxycyclohexyl)-N-(1-methyl-1H-indol-5-yl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1″ used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1-methyl-1H-indol-5-amine.

High-resolution mass (ESI+):

C₄₆H₅₁N₅O₆  Empirical formula:

[M+H]⁺ calculated: 770.3918

[M+H]⁺ measured: 770.3928

EXAMPLE 13N-(4-Hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-3-{6-[((3S)-3-[(4-methyl-1-piperazinyl)methyl]-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide bis(hydrochloride)

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1′ used in Step A by the compound ofPreparation 3′, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl % Cl⁻ Calculated 66.43 5.93 9.89 8.34 8.34 Found 66.365.79 9.83 8.11 7.67

Rotatory power: (α)_(D) ²⁰=+60.1° (c=6 mg/mL, MeOH)

EXAMPLE 14N-(4-Hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-3-{6-[((3S)-3-(1,4-oxazepan-4-ylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1′ used in Step A by the compound ofPreparation 4′, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl % CL⁻ Calculated 69.32 5.94 8.60 4.35 4.35 Found 69.245.56 8.52 4.47 4.44

EXAMPLE 15N-(4-Hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-3-{6-[((3S)-3-{[(3R)-3-methylmorpholinyl]methyl}-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1′ used in Step A by the compound ofPreparation 5′, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 69.32 5.94 8.60 4.35 Found 69.10 5.68 8.524.29

EXAMPLE 16N-(4-Hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-3-{6-[((3S)-3-{[(3S)-3-methylmorpholinyl]methyl}-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1′ used in Step A by the compound ofPreparation 6′, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 69.32 5.94 8.60 4.35 Found 68.97 5.55 8.443.73

EXAMPLE 173-{6-[((3S)-3-{[(3S,5S)-3,5-Dimethylmorpholinyl]methyl}-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1′ used in Step A by the compound ofPreparation 7′, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 69.59 6.08 8.45 4.28 Found 69.29 5.52 8.464.09

EXAMPLE 183-{5-Bromo-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 2, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

High-resolution mass (ESI+):

C₄₅H₄₄ ⁷⁹BrN₅O₄  Empirical formula:

[M+H]⁺ calculated: 798.2655

[M+H]⁺ measured: 798.2626

EXAMPLE 193-{5-Bromo-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-2,3-dihydro-1H-indol-5-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 2, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-5-indolinamine.

High-resolution mass (ESI+):

C₄₅H₄₆ ⁷⁹BrN₅O₄  Empirical formula:

[M+H]⁺ calculated: 800.2811

[M+H]⁺ measured: 800.2791

EXAMPLE 203-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-phenyl-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1 used in Step A by the compound of Preparation 3.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 68.38 5.74 7.59 4.81 Found 67.89 5.71 7.724.68

Rotatory power: (α)_(D) ²⁰=+53.7° (c=6 mg/mL, MeOH)

EXAMPLE 213-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(2,3-dihydro-1H-indol-5-yl)-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide bis(hydrochloride)

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-5-indolinamine.

High-resolution mass (ESI+):

C₄₄H₄₄ ³⁵ClN₅O₄  Empirical formula:

[M+H]⁺ calculated: 742.3160

[M+H]⁺ measured: 742.3120

EXAMPLE 223-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 68.04 5.72 8.82 4.91 Found 67.84 5.46 8.645.21

Rotatory power: (α)_(D) ²⁰=+55.9° (c=7 mg/mL, MeOH)

EXAMPLE 233-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-2,3-dihydro-1H-indol-5-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide bis(hydrochloride)

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-5-indolinamine.

Elemental microanalysis:

% C % H % N % Cl % Cl⁻ Calculated 65.18 5.83 8.45 12.83 8.55 Found 65.755.45 8.39 11.71 7.54

Rotatory power: (α)_(D) ²⁰=+56.6° (c=6 mg/mL, MeOH)

EXAMPLE 243-{5-Fluoro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 4, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 69.80 5.86 9.04 4.58 Found 69.57 5.62 8.764.47

Rotatory power: (α)_(D) ²⁰=+55.0° (c=5 mg/mL, MeOH)

EXAMPLE 253-{5-Fluoro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-phenyl-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1 used in Step A by the compound of Preparation 4.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 69.94 5.87 7.77 4.92 Found 69.70 5.32 7.724.80

EXAMPLE 263-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1,2,3,4-tetrahydro-6-quinolinamine.

Elemental microanalysis: (theory for 1.5 HCl)

% C % H % N % Cl⁻ Calculated 66.97 6.05 8.49 6.45 Found 66.80 5.55 8.326.23

EXAMPLE 273-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-amine.

Elemental microanalysis: (theory for 1.1 HCl)

% C % H % N % Cl⁻ Calculated 66.53 5.84 8.62 4.80 Found 66.59 5.39 8.474.80

EXAMPLE 283-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-[4-(diethylamino)phenyl]-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN¹-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-N⁴,N⁴-diethyl-1,4-benzenediamine.

Elemental microanalysis: (theory for 1.6 HCl)

% C % H % N % Cl⁻ Calculated 66.51 6.26 8.43 6.83 Found 66.71 5.58 8.397.08

EXAMPLE 293-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(2,3-dihydro-1H-inden-5-yl)-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C by N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-5-indanamine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 69.49 5.96 7.20 4.56 Found 69.47 5.43 7.214.21

EXAMPLE 303-{5-Chloro-2-[((3S)-3-[(4-methyl-1-piperazinyl)methyl]-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide bis(hydrochloride)

The procedure is as in the process of Example 1, replacing on the onehand the compounds of Preparations 1 and 1′ used in Step A by therespective compounds of Preparations 3 and 3′, and on the other hand thecompound of Preparation 1″ used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

High-resolution mass (ESI+):

C₄₆H₄₇ ³⁵ClN₆O₃  Empirical formula:

[M+H]⁺ calculated: 767.3476

[M+H]⁺ measured: 767.3476

EXAMPLE 31N-(4-Hydroxyphenyl)-3-{8-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-3,4-dihydro-2H-1,5-benzodioxepin-7-yl}-N-phenyl-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1 used in Step A by the compound of Preparation 5.

High-resolution mass (ESI+):

C₄₅H₄₆N₄O₆  Empirical formula:

[M+H]⁺ calculated: 739.3496

[M+H]⁺ measured: 739.3479

EXAMPLE 32N-(4-Hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-3-{8-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-3,4-dihydro-2H-1,5-benzodioxepin-7-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 5, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 69.59 6.08 8.45 4.78 Found 69.23 5.46 8.414.16

EXAMPLE 33N-(4-Hydroxyphenyl)-3-{5-methoxy-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(1-methyl-1H-indol-5-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 6, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 70.26 6.15 8.91 4.51 Found 69.78 5.36 8.904.29

Rotatory power: (α)_(D) ²⁰=+42.1° (c=6 mg/mL, MeOH)

EXAMPLE 34N-(4-Hydroxyphenyl)-3-{7-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-2,3-dihydro-1,4-benzodioxin-6-yl}-N-phenyl-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1 used in Step A by the compound of Preparation 7.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 69.42 5.96 7.36 4.66 Found 69.39 5.56 7.304.49

Rotatory power: (α)_(D) ²⁰=+34.5° (c=6 mg/mL, MeOH)

EXAMPLE 35N-(4-Hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-3-{7-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-2,3-dihydro-1,4-benzodioxin-6-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 7, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine,it being understood that the product so obtained is not subjected to astep of salt formation in the presence of etheral hydrogen chloride.

Elemental microanalysis:

% C % H % N Calculated 72.57 6.09 9.00 Found 73.11 5.70 8.95

Rotatory power: (α)_(D) ²⁰=+88.2° (c=7 mg/mL, MeOH)

EXAMPLE 363-{5-Ethoxy-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 8, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl Calculated 70.53 6.30 8.75 4.43 Found 70.77 5.59 8.664.22

EXAMPLE 37N-(4-Hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-3-{2,2-dideuterio-6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 9, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

High-resolution mass (ESI+):

C₄₆H₄₃N₅O₆D₂  Empirical formula:

[M+H]⁺ calculated: 766.3573

[M+H]⁺ measured: 766.3533

Rotatory power: (α)_(D) ²⁰=+35.5° (c=3.5 mg/mL, MeOH)

EXAMPLE 38N-(4-Hydroxyphenyl)-3-{2,2-dideuterio-6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-N-phenyl-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride Step A:N-(4-Hydroxyphenyl)-3-{2,2-dideuterio-6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-N-phenyl-5,6,7,8-tetrahydro-1-indolizinecarboxamide

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1 used in Step A by the compound of Preparation 9, itbeing understood that the step of salt formation in the presence ofethereal hydrogen chloride is carried out only in the following Step B.

Step B:N-(4-Hydroxyphenyl)-3-{2,2-dideuterio-6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-N-phenyl-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The product obtained in Step A is dissolved in dichloromethane, and 2 mLof 1N ethereal hydrogen chloride are added. The whole is stirred for onehour and then evaporated to dryness. The hydrochloride so obtained isdissolved in a water/acetonitrile mixture until completely dissolved,and is then lyophilised.

Elemental microanalysis:

% C % H % N % Cl % Cl⁻ Calculated 68.93 5.80 7.48 4.73 4.73 Found 68.455.49 7.57 4.63 4.54

EXAMPLE 39N-(4-Hydroxyphenyl)-N-(1-methyl-1H-indazol-5-yl)-3-{7-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-2,3-dihydro-1,4-benzodioxin-6-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 7, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indazol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 67.76 5.81 10.31 4.35 Found 67.82 5.25 9.874.18

Rotatory power: (α)_(D) ²⁰=+42.6° (c=5 mg/mL, MeOH)

EXAMPLE 40N-(4-Hydroxyphenyl)-N-(1-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-3-{7-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-2,3-dihydro-1,4-benzodioxin-6-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 7, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1,2,3,4-tetrahydro-6-quinolinamine.

Elemental microanalysis:

% C % H % N % Cl % Cl⁻ Calculated 66.51 6.16 8.08 8.18 8.18 Found 66.855.88 8.04 6.47 6.25

EXAMPLE 41N-(4-Hydroxyphenyl)-N-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-3-{7-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-2,3-dihydro-1,4-benzodioxin-6-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 7, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-amine.

High-resolution mass (ESI+):

C₄₇H₄₉N₅O₇  Empirical formula:

[M+H]⁺ calculated: 796.3710

[M+H]⁺ measured: 796.3687

EXAMPLE 423-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indazol-5-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indazol-5-amine.

Elemental microanalysis:

% C % H % N % Cl % Cl⁻ Calculated 66.75 5.60 10.61 8.96 4.48 Found 66.635.06 10.42 8.83 4.46

EXAMPLE 431-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-2,3-dihydro-1H-indol-5-yl)-5,6,7,8-tetrahydro-3-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 24, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl Calculated 68.35 5.74 8.86 8.97 Found 68.29 5.21 8.769.04

EXAMPLE 443-{5-Fluoro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indazol-5-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 4, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indazol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 68.16 5.72 10.84 4.57 Found 67.93 5.0110.89 4.24

EXAMPLE 453-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1′-methyl-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-5′-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-(1′-methyl-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-5′-yl)amine.

Elemental microanalysis:

% C % H % N Calculated 72.15 6.18 8.95 Found 71.86 5.76 8.85

EXAMPLE 463-{5-Chloro-2-[((3S)-3-(1,4-oxazepan-4-ylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compounds of Preparations 1 and 1′ used in Step A by therespective compounds of Preparations 3 and 4′, and on the other hand thecompound of Preparation 1″ used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N Calculated 68.65 5.89 8.70 Found 68.33 5.45 8.54

Rotatory power: (α)_(D) ²⁰=+13.6° (c=4 mg/mL, MeOH)

EXAMPLE 47N-(4-Hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-3-[2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-5-(trifluoromethyl)-phenyl]-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 10, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 67.02 5.50 8.50 4.30 Found 67.01 5.11 8.474.21

EXAMPLE 48N-(4-Hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-3-[2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-5-(trifluoromethoxy)-phenyl]-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 11, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl % Cl⁻ Calculated 65.75 5.40 8.33 4.22 4.22 Found 65.785.00 8.35 4.33 4.50

EXAMPLE 493-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1,3,3-trimethyl-2,3-dihydro-1H-indol-5-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1,3,3-trimethyl-5-indolinamine,it being understood that the product so obtained is not subjected to astep of salt formation in the presence of ethereal hydrogen chloride.

Elemental microanalysis:

% C % H % N Calculated 71.97 6.42 8.93 Found 71.87 6.22 8.94

EXAMPLE 50N-(4-Hydroxyphenyl)-N-(1-methyl-1H-indazol-5-yl)-3-{2,2-dideuterio-6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 9, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indazol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 67.28 5.66 10.46 4.41 Found 66.77 5.0710.25 3.92

EXAMPLE 51N-(3-Fluoro-4-methylphenyl)-N-(4-hydroxyphenyl)-3-{2,2-dideuterio-6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 9, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-fluoro-4-methylaniline.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 67.64 5.69 7.17 4.54 Found 67.08 5.18 7.044.28

EXAMPLE 523-{5-Chloro-2-[((3S)-3-[(dimethylamino)methyl]-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compounds of Preparations 1 and 1′ used in Step A by therespective compounds of Preparations 3 and 8′, and on the other hand thecompound of Preparation 1″ used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

High-resolution mass (ESI+):

C₄₃H₄₂ ³⁵ClN₅O₃  Empirical formula:

[M+H]⁺ calculated: 712.3054

[M+H]⁺ measured: 712.3060

Rotatory power: (α)_(D) ²⁰=+35.8° (c=6 mg/mL, MeOH)

EXAMPLE 533-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-[4-methoxy-3-(trifluoro-methyl)phenyl]-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4-methoxy-3-(trifluoromethyl)aniline.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 63.23 5.19 6.70 4.24 Found 63.08 4.68 6.793.92

EXAMPLE 543-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-[4-(methylsulphanyl)-3-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4-(methylsulphanyl)-3-(trifluoromethyl)aniline.

Elemental microanalysis:

% C % H % N % S % Cl⁻ Calculated 62.04 5.09 6.58 3.76 4.16 Found 62.104.90 6.61 3.37 3.99

EXAMPLE 553-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(3-fluoro-4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-fluorophenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 66.83 5.48 8.66 4.38 Found 66.84 4.92 8.683.63

EXAMPLE 56N-(4-Hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-3-{2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 12, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 71.84 5.63 9.31 4.71 Found 71.74 5.25 9.244.38

EXAMPLE 57N-(4-Hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-3-{6-[((3S)-3-[(4-methyl-1-piperazinyl)methyl]-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-1-indolizinecarboxamide bis(hydrochloride)

The procedure is as in the process of Example 1, replacing on the onehand the compounds of Preparations 1 and 1′ used in Step A by therespective compounds of Preparations 13 and 3′, and on the other handthe compound of Preparation 1″ used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 66.74 5.48 9.94 8.38 Found 66.69 5.25 9.808.03

Rotatory power: (α)_(D) ²⁰=+113.2° (c=6 mg/mL, MeOH)

EXAMPLE 58N-(4-Hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-N-phenyl-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 13.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 69.49 5.29 7.54 4.77 Found 69.41 5.00 7.614.45

Rotatory power: (α)_(D) ²⁰=+111.4° (c=6 mg/mL, MeOH)

EXAMPLE 59N-(4-Hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 13, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 69.38 5.32 8.79 4.45 Found 68.95 5.12 8.573.92

Rotatory power: (α)_(D) ²⁰=+116.8° (c=5 mg/mL, MeOH)

EXAMPLE 60N-(1-Ethyl-1H-indol-5-yl)-N-(4-hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 13, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-ethyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 69.66 5.47 8.64 4.38 Found 69.81 5.13 8.644.30

EXAMPLE 61N-(4-Hydroxyphenyl)-N-(1-methyl-2,3-dihydro-1H-indol-5-yl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 13, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-5-indolinamine.

High-resolution mass (ESI+):

C₄₆H₄₃N₅O₆  Empirical formula:

[M+H]⁺ calculated: 762.3292

[M+H]⁺ measured: 762.3284

EXAMPLE 62N-(4-Hydroxyphenyl)-N-(1-isopropyl-1H-indol-5-yl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 13, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-isopropyl-1H-indol-5-amine.

Elemental microanalysis: (theory for 1.3 HCl)

% C % H % N % Cl⁻ Calculated 69.94 5.62 8.50 4.30 Found 69.66 5.50 8.424.28

EXAMPLE 63N-(1-Ethyl-2,3-dihydro-1H-indol-5-yl)-N-(4-hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 13, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-ethyl-5-indolinamine.

Elemental microanalysis: (theory for 1.3 HCl)

% C % H % N % Cl⁻ Calculated 68.57 5.67 8.51 5.60 Found 68.11 5.23 8.365.65

EXAMPLE 64N-(4-Hydroxyphenyl)-N-(1-isopropyl-2,3-dihydro-1H-indol-5-yl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 13, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-isopropyl-5-indolinamine.

Elemental microanalysis: (theory for 1.3 HCl)

% C % H % N % Cl⁻ Calculated 68.85 5.81 8.36 5.50 Found 68.58 5.68 8.495.10

EXAMPLE 653-{5-Chloro-2-[((3S)-3-[(4-methyl-1-piperazinyl)methyl]-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-1-indolizinecarboxamide bis(hydrochloride)

The procedure is as in the process of Example 1, replacing on the onehand the compounds of Preparations 1 and 1′ used in Step A by therespective compounds of Preparations 14 and 3′, and on the other handthe compound of Preparation 1″ used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis: (theory for 1.9 HCl)

% C % H % N % Cl⁻ Calculated 66.36 5.44 10.09 8.09 Found 66.35 5.38 9.867.70

EXAMPLE 663-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-2,3-dihydro-1H-indol-5-yl)-1-indolizinecarboxamide bis(hydrochloride)

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 14, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-5-indolinamine.

Elemental microanalysis:

% C % H % N % Cl Calculated 65.50 5.37 8.49 12.89 Found 66.02 4.91 8.5012.11

Rotatory power: (α)_(D) ²⁰=+142.2° (c=3.5 mg/mL, MeOH)

EXAMPLE 673-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carhonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 14, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 68.70 5.25 8.90 4.51 Found 68.43 4.88 8.834.13

Rotatory power: (α)_(D) ²⁰=+133.3° (c=3.5 mg/mL, MeOH)

EXAMPLE 683-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-fluorophenyl)-N-(1-methyl-1H-indol-5-yl)-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 14, and on the other hand the compound of Preparation 1″used in Step C by N-(4-fluorophenyl)-1-methyl-1H-indol-5-amine, it beingunderstood that step D is then limited to a step of formation of thehydrochloride.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 68.53 5.11 8.88 4.49 Found 68.48 4.71 9.094.28

EXAMPLE 69N-(4-Hydroxyphenyl)-N-(1-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-3-{7-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-2,3-dihydro-1,4-benzodioxin-6-yl}-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 15, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1,2,3,4-tetrahydro-6-quinolinamine.

High-resolution mass (ESI+):

C₄₈H₄₇N₅O₆  Empirical formula:

[M+H]⁺ calculated: 790.3605

[M+H]⁺ measured: 790.3591

EXAMPLE 70N-(4-Hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-3-{7-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-2,3-dihydro-1,4-benzodioxin-6-yl}-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 15, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl % Cl⁻ Calculated 69.66 5.47 8.64 4.38 4.38 Found 69.454.68 8.56 4.64 4.21

EXAMPLE 71N-(4-Hydroxyphenyl)-3-{5-methoxy-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(1-methyl-1H-indol-5-yl)-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 16, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

High-resolution mass (ESI+):

C₄₆H₄₃N₅O₅  Empirical formula:

[M+H]⁺ calculated: 746.3342

[M+H]⁺ measured: 746.3348

EXAMPLE 72 Tert-butyl8-{([4-hydroxy(1-methyl-1H-indol-5-yl)anilino]carbonyl}-6-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 17, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine,it being understood that the product so obtained is not subjected to astep of salt formation in the presence of ethereal hydrogen chloride.

Elemental microanalysis:

% C % H % N Calculated 69.43 6.06 9.72 Found 69.41 5.84 9.68

EXAMPLE 73 Tert-butyl8-{[4-hydroxy(1-methyl-2,3-dihydro-1H-indol-5-yl)anilino]-carbonyl}-6-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)-carbonyl]-1,3-benzodioxol-5-yl}-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 17, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-5-indolinamine, itbeing understood that the product so obtained is not subjected to a stepof salt formation in the presence of ethereal hydrogen chloride.

Elemental microanalysis:

% C % H % N Calculated 69.27 6.28 9.69 Found 69.20 6.11 9.77

EXAMPLE 74N-(4-Hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-6-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamidebis(hydrochloride)

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 17, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine,it being understood that the product so obtained is not subjected to astep of salt formation in the presence of ethereal hydrogen chloride asdescribed in Example 1, Step D. The compound so obtained is deprotectedin the presence of 10 equivalents of trifluoroacetic acid indichloromethane (10 mL/mmol) at ambient temperature overnight. Then, theproduct is subsequently isolated by concentrating the reaction mixtureto dryness. It is finally subjected to a step of salt formation in thepresence of ethereal hydrogen chloride.

Elemental microanalysis: (theory for 1.9 HCl)

% C % H % N % Cl⁻ Calculated 64.80 5.55 10.08 8.08 Found 64.48 5.41 9.857.84

EXAMPLE 75N-(4-Hydroxyphenyl)-N-(1-methyl-2,3-dihydro-1H-indol-5-yl)-6-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamidetris(hydrochloride)

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 17, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-5-indolinamine, itbeing understood that the product so obtained is not subjected to a stepof salt formation in the presence of ethereal hydrogen chloride asdescribed in Example 1, Step D. The compound so obtained is deprotectedin the presence of 10 equivalents of trifluoroacetic acid indichloromethane (10 mL/mmol) at ambient temperature overnight. Then, theproduct is subsequently isolated by concentrating the reaction mixtureto dryness. It is finally subjected to a step of salt formation in thepresence of ethereal hydrogen chloride.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 61.68 5.64 9.59 12.14 Found 61.65 5.35 9.4511.72

EXAMPLE 76N-(4-Hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-5-{6-[((3S)-3-[(4-methyl-1-piperazinyl)methyl]-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-2,3-dihydro-1H-pyrrolizine-7-carboxamidebis(hydrochloride)

The procedure is as in the process of Example 1, replacing on the onehand the compounds of Preparations 1 and 1′ used in Step A by therespective compounds of Preparations 18 and 3′, and on the other handthe compound of Preparation 1″ used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

High-resolution mass (ESI+):

C₄₆H₄₆N₆O₅  Empirical formula:

[M+H]⁺ calculated: 763.3608

[M+H]⁺ measured: 763.3594

EXAMPLE 775-{5-Chloro-2-[((3S)-3-[(4-methyl-1-piperazinyl)methyl]-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-2,3-dihydro-1H-pyrrolizine-7-carboxamidebis(hydrochloride)

The procedure is as in the process of Example 1, replacing on the onehand the compounds of Preparations 1 and 1′ used in Step A by therespective compounds of Preparations 19 and 3′, and on the other handthe compound of Preparation 1″ used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis: (theory for 1.9 HCl)

% C % H % N % Cl⁻ Calculated 65.70 5.75 10.22 8.19 Found 65.46 5.5510.68 7.65

EXAMPLE 786-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1 used in Step A by the compound of Preparation 20.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 66.57 5.45 7.57 4.79 Found 66.22 5.23 7.534.57

EXAMPLE 796-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(2,3-dihydro-1H-indol-5-yl)-N-(4-hydroxyphenyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamidebis(hydrochloride)

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 20, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-5-indolinamine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 63.20 5.43 8.57 8.68 Found 62.64 5.19 8.398.03

EXAMPLE 80N-(4-Hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-6-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 21, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine,it being understood that the product so obtained is not subjected to astep of salt formation in the presence of ethereal hydrogen chloride.

Elemental microanalysis:

% C % H % N Calculated 70.57 5.66 9.14 Found 69.99 5.53 9.04

EXAMPLE 81N-(4-Hydroxyphenyl)-N-(1-methyl-2,3-dihydro-1H-indol-5-yl)-6-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 21, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-5-indolinamine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 67.20 5.76 8.71 4.41 Found 66.67 5.60 8.665.10

EXAMPLE 826-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(3-fluoro-4-methylphenyl)-N-(4-hydroxyphenyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 20, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-fluoro-4-methylaniline.

Elemental microanalysis:

% C % H % N % Cl % Cl⁻ Calculated 65.37 5.35 7.26 9.19 4.59 Found 65.494.67 7.45 9.18 4.40

Rotatory power: (α)_(D) ²⁰=+35.0° (c=6 mg/mL, MeOH)

EXAMPLE 833-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carhonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-6-yl)-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 22, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

High-resolution mass (ESI+):

C₄₆H₄₆ ³⁵ClN₅O₄  Empirical formula:

[M+H]⁺ calculated: 768.3317

[M+H]⁺ measured: 768.3254

EXAMPLE 84N-(4-Hydroxyphenyl)-N-(1-methyl-1H-indol-6-yl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 23, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 69.32 5.94 8.60 4.35 Found 69.42 5.52 8.744.05

Rotatory power: (α)_(D) ²⁰=+86.6° (c=8 mg/mL, MeOH)

EXAMPLE 853-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(3-thienyl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-thiophenamine.

Elemental microanalysis:

% C % H % N % S % Cl⁻ Calculated 64.60 5.42 7.53 4.31 4.77 Found 64.675.05 7.37 3.90 4.19

EXAMPLE 866-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 20, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

High-resolution mass (ESI+):

C₄₄H₄₂ ³⁵ClN₅O₅  Empirical formula:

[M+H]⁺ calculated: 756.2953

[M+H]⁺ measured: 756.2936

EXAMPLE 87N-Butyl-N-(4-hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1″ used in Step C byN-butyl-4-{[tert-butyl(dimethyl)silyl]oxy}aniline.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 67.71 6.51 7.70 4.87 Found 67.48 6.30 7.745.01

EXAMPLE 88N-Butyl-N-[(3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinyl)-methyl]-1-butanaminehydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1″ used in Step C by 1a N,N-dibutylamine, it beingunderstood that Step D is then limited to a step of formation of thehydrochloride.

High-resolution mass (ESI+):

C₃₉H₅₀N₄O₅  Empirical formula:

[M+H]⁺ calculated: 655.3859

[M+H]⁺ measured: 655.3826

EXAMPLE 893-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(3-hydroxypropyl)-N-(1-methyl-1H-indol-5-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl % Cl⁻ Calculated 66.66 6.26 9.25 9.37 4.68 Found 66.515.87 9.25 9.12 4.21

EXAMPLE 903-{5-Chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxybutyl)-N-(1-methyl-1H-indol-5-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide hydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(3-{[tert-butyl(dimethyl)silyl]oxy}butyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 67.01 6.41 9.09 4.60 Found 66.93 5.88 9.234.30

EXAMPLE 91N-(3-Fluoro-4-methylphenyl)-3-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 4, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-fluoro-4-methylaniline.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 68.56 5.75 7.44 4.71 Found 68.57 5.23 7.534.74

EXAMPLE 92N-(3-Fluoro-4-methylphenyl)-N-(4-hydroxyphenyl)-6-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 21, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-fluoro-4-methylaniline.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 66.11 5.42 7.17 4.54 Found 66.02 4.92 7.134.26

EXAMPLE 933-(5-Chloro-2-{[(3R)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compounds of Preparations 1 and 1′ used in Step A by thecompounds of Preparations 3 and 2′, and on the other hand the compoundof Preparation 1″ used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl % Cl⁻ Calculated 68.35 5.74 8.86 8.97 4.48 Found 68.275.14 8.92 8.70 4.08

EXAMPLE 94N-(4-Hydroxyphenyl)-N-(1-methyl-1H-indazol-5-yl)-3-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1″ used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indazol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 67.45 5.66 10.49 4.42 Found 67.40 5.1910.40 4.11

EXAMPLE 95N-(4-Hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-3-(5-methyl-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 25, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 71.72 6.28 9.09 4.60 Found 71.17 5.66 8.854.47

EXAMPLE 96N-(4-Hydroxyphenyl)-N-(1-meth-1H-indol-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-2,3-dihydro-1H-pyrrolizine-7-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 18, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 68.74 5.64 8.91 4.51 Found 68.41 4.96 8.844.31

EXAMPLE 97N-(3-Chloro-4-methylphenyl)-3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-chloro-4-methylaniline.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 65.69 5.51 7.13 4.51 Found 65.58 5.03 7.054.25

EXAMPLE 98N-(3-Fluoro-4-methylphenyl)-6-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 26, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-fluoro-4-methylaniline.

High-resolution mass (ESI+):

C₄₂H₄₀F₂N₄O₅  Empirical formula:

[M+H]⁺ calculated: 719.3045

[M+H]⁺ measured: 719.3030

EXAMPLE 996-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-fluorophenyl)-N-(4-hydroxyphenyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 26, and on the other hand the compound of Preparation 1″used in Step C by4-{[tert-butyl(dimethyl)silyl]oxy}-N-(4-fluorophenyl)aniline.

High-resolution mass (ESI+):

C₄₁H₃₈F₂N₄O₅  Empirical formula:

[M+H]⁺ calculated: 705.2889

[M+H]⁺ measured: 705.2882

EXAMPLE 1003-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-7-hydroxy-N-(4-hydroxyphenyl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride Step A: Methyl3′-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-5′,6′-dihydro-8′H-spiro[1,3-dioxolane-2,7′-indolizine]-1′-carboxylate

The procedure is as in the process of Step A of Example 1, replacing thecompound of Preparation 1 by the compound of Preparation 27.

Step B: Methyl3-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-7-(prop-2-en-1-yloxy)-5,6,7,8-tetrahydroindolizine-1-carboxylate

The procedure is as in the process of Steps B, C and D of Example 113.

Step C:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-3-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-phenyl-7-(prop-2-en-1-yloxy)-5,6,7,8-tetrahydroindolizine-1-carboxamide

The procedure is as in the processes of Steps B and C of Example 1.

Step D:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-3-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-phenyl-7-hydroxy-5,6,7,8-tetrahydroindolizine-1-carboxamide

There is subsequently carried out a reaction of deprotection of theallyl group in the presence of1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (also called dimethylbarbiturate) and of tetrakis(triphenylphosphine)palladium in a mixtureof methanol and dichloromethane.

Step E:3-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-7-hydroxy-N-(4-hydroxyphenyl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

Deprotection of the tert-butylsilyloxy group is carried out according tothe process of Step D of Example 1.

Elemental microanalysis:

% C % H % N Calculated 71.98 5.90 7.99 Found 71.18 5.98 7.18

High-resolution mass (ESI+):

C₄₂H₄₂FN₄O₅  Empirical formula:

[M+H]⁺ calculated: 701.3139

[M+H]⁺ measured: 701.3134

EXAMPLE 1016-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indazol-5-yl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 20, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indazol-5-amine.

Elemental microanalysis:

% C % H % N Calculated 65.07 5.33 10.59 Found 65.54 4.86 10.57

EXAMPLE 102(2R)-5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-2-hydroxy-N-(4-hydroxyphenyl)-N-phenyl-2,3-dihydro-1H-pyrrolizine-7-carboxamidehydrochloride Step A:Methyl(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-2,3-dihydro-1H-pyrrolizine-7-carboxylate

The procedure is as in the process of Step A of Example 1, replacing thecompound of Preparation 1 by the compound of Preparation 28.

Step B:Methyl(2R)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-2-hydroxy-2,3-dihydro-1H-pyrrolizine-7-carboxylate

To a solution of the compound of Step A (1 g; 1.54 mmol) in THF (8 mL)there is added a 1 M tetrabutylammonium fluoride solution (1.7 mL; 1.7mmol). The reaction mixture is stirred for 3 hours at ambienttemperature, and then the THF is evaporated off and replaced by ethylacetate. The organic phase is washed with water and then with brine,before being dried over MgSO₄, filtered and concentrated to dryness. Thecrude product obtained (830 mg) is used as such in the following step.

¹H-NMR: δ (500 MHz; dmso-d6; 300° K) 7.55-6.9 (m, 7H, H aromatic);6.55-6.35 (m, 1H, H aromatic dihydropyrrolizine); 5.5-5.3 (m, 1H,alcohol); 5.25-4.6 (m, 1H, H tertiary tetrahydroisoquinoline); 5.0-4.2(m, 2H, H aliphatic tetrahydroisoquinoline); 4.95-4.62 (m, 1H, HCOH);3.7-3.6 (sl, 3H, OMe); 3.6-3.2. (m, 2H, 2H, H aliphaticdihydropyrrolizine); 3.7-3.5 (m, 4H, H morpholine); 3.0-2.4 (m, 2H, Haliphatic tetrahydroisoquinoline); 2.6-1.96 (m, 4H, H morpholine);2.6-1.96 (m, 2H, H aliphatic dihydropyrrolizine)

Step C:Methyl(2R)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-2-(prop-2-en-1-yloxy)-2,3-dihydro-1H-pyrrolizine-7-carboxylate

To a suspension of 62 mg (1.54 mmol) of sodium hydride in 8 mL ofanhydrous THF cooled to 0° C. there is added a solution of the compoundof Step B (820 mg; 1.54 mmol) in THF (6 mL). The suspension is stirredfor 15 minutes at 0° C. There is subsequently added 0.15 mL (1.69 mmol)of allyl bromide, dropwise. The reaction mixture is stirred for 5 hoursat ambient temperature, and then hydrolysed with a saturated aqueoussodium bicarbonate solution and extracted with dichloromethane. Theorganic phase is dried over MgSO₄, filtered and concentrated to dryness.The oil so obtained is purified by flash chromatography (gradient:dichloromethane/ammoniacal methanol) to yield the title product in solidform.

¹H-NMR: δ (500 MHz; dmso-d6; 300° K): 7.5-6.8 (m, 7H, H aromatic);6.55-6.3 (m, 1H, H aromatic dihydropyrrolizine); 5.9 (s, 1H, H allyl);5.3-5.2 (m, 2H, H allyl); 5.2-5.0 (m, 1H, H tertiarytetrahydroisoquinoline); 5.0-4.2 (m, 2H, H aliphatictetrahydroindolizine); 4.7-4.42 (m, 1H, HCO allyl); 4.6-3.85 (m, 2H, Haliphatic dihydropyrrolizine); 4.6-3.85 (m, 2H, CH2 allylic); 3.7-3.5(m, 3H, OMe); 3.65-3.5 (m, 4H, morpholine); 3.3-2.4 (m, 4H, morpholineand H aliphatic dihydropyrrolidine); 2.4-1.7 (m, 6H, morpholine andCH₂N)

Step D:(2R)—N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-phenyl-2-(prop-2-en-1-yloxy)-2,3-dihydro-1H-pyrrolizine-7-carboxamide

The procedure is as in the processes of Steps B and C of Example 1.

Step E:(2R)—N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-2-hydroxy-N-phenyl-2,3-dihydro-1H-pyrrolizine-7-carboxamide

There is then carried out a reaction of deprotection of the allyl groupin the presence of 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (alsocalled dimethyl barbiturate) and oftetrakis(triphenylphosphine)palladium (Synlett, 2007, 21, p. 3136).

Step F:(2R)-5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-2-hydroxy-N-(4-hydroxyphenyl)-N-phenyl-2,3-dihydro-1H-pyrrolizine-7-carboxamidehydrochloride

Deprotection of the tert-butylsilyloxy group is carried out according tothe process of Step D of Example 1.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 68.09 5.57 7.75 4.90 Found 67.73 5.10 7.544.84

High-resolution mass (ESI+):

C₄₁FH₃₉N₄O₅  Empirical formula:

[M+H]⁺ calculated: 687.2983

[M+H]⁺ measured: 687.2958

EXAMPLE 1033-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamide

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-amine.

High-resolution mass (ESI+):

C₄₄ClH₄₄N₆O₄  Empirical formula:

[M+H]⁺ calculated: 755.3113

[M+H]⁺ measured: 755.3088

EXAMPLE 104N-(4-Hydroxyphenyl)-3-(5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(1-methyl-1H-indazol-5-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 6, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indazol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 68.65 6.02 10.67 4.50 Found 67.91 5.5210.53 4.08

EXAMPLE 105N-(4-Hydroxyphenyl)-3-(6-{[(3S)-3-{[4-(2-methoxyethyl)piperazin-1-yl]methyl}-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamidebis(hydrochloride)

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1′ used in Step A by the compound of Preparation 9′.

Elemental microanalysis:

% C % H % N Calculated 65.71 6.11 8.33 Found 66.57 6.16 8.44

EXAMPLE 106(2S)-5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-2-hydroxy-N-(4-hydroxyphenyl)-N-phenyl-2,3-dihydro-1H-pyrrolizine-7-carboxamidehydrochloride

The procedure is as in the process of Example 102 replacing the compoundof Preparation 28 used in Step A by the compound of Preparation 29.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 68.09 5.57 7.75 4.90 Found 68.16 5.13 7.744.97

EXAMPLE 1073-(5-Chloro-2-{[(3S)-3-[(4-methyl-3-oxopiperazin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compounds of Preparations 1 and 1′ used in Step A by therespective compounds of Preparations 3 and 10′, and on the other handthe compound of Preparation 1″ used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl % Cl⁻ Calculated 67.56 5.67 10.28 8.67 4.34 Found 67.315.14 10.18 8.27 3.76

EXAMPLE 1083-(5-Chloro-2-{[(3S)-3-{[(2-methoxyethyl)(methyl)amino]methyl}-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compounds of Preparations 1 and 1′ used in Step A by therespective compounds of Preparations 3 and 11′, and on the other handthe compound of Preparation 1″ used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis

% C % H % N % Cl⁻ Calculated 68.18 5.98 8.83 4.47 Found 68.30 5.61 8.784.46

EXAMPLE 109N-(4-Hydroxyphenyl)-3-(6-{[(3S)-3-[(4-oxidomorpholin-4-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide

To a solution of the compound of Example 1, taken in the form of thefree base, in 10 mL of CH₂Cl₂ there is added in portionsmeta-chloroperbenzoic acid (0.242 mg; 1.4 mmol). The whole issubsequently stirred at ambient temperature overnight. The reactionmixture is subsequently concentrated to dryness, and then the residue ispurified by reverse-phase flash chromatography (gradient:acetonitrile/water/trifluoroacetic acid). There is obtained, afterconcentration, the title product in the form of a solid.

Elemental microanalysis:

% C % H % N Calculated 71.06 5.82 7.71 Found 70.59 5.36 7.69

High-resolution mass (ESI+):

C₄₃H₄₂N₄O₇  Empirical formula:

[M+H]⁺ calculated: 727.3132

[M+H]⁺ measured: 727.3110

EXAMPLE 1103-(5-Chloro-2-{[(3S)-3-{[ethyl(2-methoxyethyl)amino]methyl}-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compounds of Preparations 1 and 1′ used in Step A by therespective compounds of Preparations 3 and 12′, and on the other handthe compound of Preparation 1″ used in Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 68.48 6.12 8.68 4.39 Found 68.40 5.78 8.614.23

EXAMPLE 1113-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-fluorophenyl)-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C by4-{[tert-butyl(dimethyl)silyl]oxy}-N-(4-fluorophenyl)aniline.

High-resolution mass (ESI+):

C₄₂H₄₀ClN₄O₄  Empirical formula:

[M+H]⁺ calculated: 719.2722

[M+H]⁺ measured: 719.2806

EXAMPLE 112N-(4-Hydroxyphenyl)-3-(5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1 used in Step A by the compound of Preparation 6.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 70.43 6.19 7.64 4.83 Found 70.17 5.79 7.604.69

EXAMPLE 1137-Hydroxy-N-(4-hydroxyphenyl)-3-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride Step A: Methyl3′-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-5′,6′-dihydro-8′H-spiro[1,3-dioxolane-2,7′-indolizine]-1′-carboxylate

The procedure is as in the process of Step A of Example 1, replacing thecompound of Preparation 1 by the compound of Preparation 30.

Step B: Methyl3-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-7-oxo-5,6,7,8-tetrahydroindolizine-1-carboxylate

2.75 g of the compound of Step A (4.47 mmol) in solution in 75 mL of THFare stirred in the presence of 37 mL of 1 M HCl at reflux for 15 hours.100 mL of water and 100 mL of ethyl acetate are added to the reactionmixture. There are subsequently added 4 g of NaHCO₃ (4.7 mmol) in powderform until a basic pH is reached. The compound is extracted with ethylacetate, and the organic phase is dried over MgSO₄, filtered andconcentrated to dryness. The title product is obtained in the form of anoil.

¹H-NMR: δ (500 MHz; dmso-d6; 300° K): 7.9-7.2 (m, 4H, H aromatic); 7.02(m, 1H, H aromatic); 6.88 (m, 1H, H aromatic); 6.44-5.87 (m, 1H, Haromatic tetrahydroindolizine); 6.17 (d, 2H, CH₂ methylenedioxy);5.07/4.85/3.79 (m, 1H, H tertiary tetrahydroisoquinoline);4.88/4.27/4.24 (m, 2H, H aliphatic tetrahydroisoquinoline); 4.22-3.43(m, 4H, H aliphatic tetrahydroindolizine); 3.59-3.49 (m, 4H, H aliphaticmorpholine); 3.75-3.52 (s, 3H, Me); 2.93-2.49 (m, 2H, H aliphatictetrahydroindolizine); 2.75-2.28 (m, 2H, H aliphatictetrahydroindolizine); 2.68-1.68 (m, 6H, H aliphatic morpholine+CH₂)

Step C: Methyl7-hydroxy-3-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1-carboxylate

To a solution of 2.55 g of the compound obtained in Step B (4.47 mmol)in 30 mL of methanol there are added in portions 558 mg (14.75 mmol) ofsodium borohydride. The reaction mixture is stirred for one hour atambient temperature. 50 mL of 1M HCl are subsequently added, and themethanol is evaporated off. The aqueous phase is subsequentlyneutralised with NaHCO₃ and then extracted with dichloromethane. Theorganic phase is washed in succession with H₂O, dried over MgSO₄,filtered and concentrated to dryness. The oil so obtained is purified byflash chromatography (dichloromethane/ethanol-ammonia gradient). Thetitle product is obtained in the form of a solid.

¹H-NMR: δ (500 MHz; dmso-d6; 300° K): 7.22-6.97 (m, 4H, H aromatictetrahydroisoquinoline); 7.05 (s, 1H, H aromatic); 6.89 (s, 1H, Haromatic); 6.37/6.3/6.07 (m, 1H, H aromatic tetrahydroindolizine); 6.16(d, 2H, CH₂ methylenedioxy); 5.09 (m, 1H, H tertiarytetrahydroisoquinoline); 4.87-4.21 (m, 2H, H aliphatictetrahydroindolizine); 4.20-3.67 (m, 2H, H aliphatictetrahydroindolizine); 4.10-3.86 (m, 1H, H tertiarytetrahydroindolizine); 3.69-3.58 (s, 3H, Me); 3.69-3.52 (m, 4H, Haliphatic morpholine); 2.96+2.43 (m, 2H, H aliphatictetrahydroisoquinoline); 2.55-2.0 (m, 6H, H aliphatic morpholine+CH₂);2.4-1.5 (m, 4H, H aliphatic tetrahydroindolizine)

IR: OH: 3239 cm⁻¹; —C═O (ester): 1696 cm⁻¹; —C═O (amide): 1624 cm⁻¹;C—C—OH (secondary alcohol): 1034 cm⁻¹

Step D: Methyl3-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-7-(prop-2-en-1-yloxy)-5,6,7,8-tetrahydroindolizine-1-carboxylate

To a suspension of 331 mg (8.26 mmol) of sodium hydride in 15 mL ofanhydrous THF cooled to 0° C. there are added 2.37 g (4.13 mmol) of thecompound obtained in Step C. The suspension is stirred for 15 minutes at0° C., and then a solution of 790 μL (9.1 mmol) of allyl bromide in 10mL of THF is added slowly (over a period of 15 minutes). The reactionmixture is stirred for one hour at 0° C. and then for 15 hours atambient temperature. The solution is hydrolysed with a saturated aqueousNH₄Cl solution. The compound is extracted with ethyl acetate; theorganic phase is dried over MgSO₄, filtered and concentrated to dryness.The oil so obtained is purified by flash chromatography(cyclohexane/ethyl acetate gradient). The title product is obtained inthe form of a solid.

¹H-NMR: δ (500 MHz; dmso-d6; 300° K): 7.2-6.9 (m, 4H, H aromatictetrahydroisoquinoline); 7.2-6.8 (m, 2H, H aromatic); 6.4-6.0 (m, 1H, Haromatic tetrahydroindolizine); 6.10 (d, 2H, CH₂ methylenedioxy); 5.9(m, 1H, allyl); 5.35-5.10 (m, 2H, allyl); 5.1+4.75 (m, 1H, H tertiarytetrahydroisoquinoline); 4.15-3.9 (m, 2H, CH₂ allyl); 3.9-3.6 (m, 1H, Htertiary tetrahydroindolizine); 4.1-3.4 (m, 4H, H aliphatic morpholine);4.9-3.4 (m, 4H, 2H aliphatic tetrahydroindolizine+2H aliphatictetrahydroisoquinoline); 3.8-3.6 (s, 3H, Me); 2.55-1.6 (m, 6H, Haliphatic morpholine+CH₂); 3.3-1.5 (m, 6H, 4H aliphatictetrahydroindolizine+2H aliphatic tetrahydroisoquinoline)

Step E:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-3-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-7-(prop-2-en-1-yloxy)-5,6,7,8-tetrahydroindolizine-1-carboxamide

The procedure is as in the processes of Steps B and C of Example 1.

Step F:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-7-hydroxy-3-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide

There is then carried out a reaction of deprotection of the allyl groupin the presence of 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (alsocalled dimethyl barbiturate) and oftetrakis(triphenylphosphine)palladium in a mixture of methanol anddichloromethane.

Step G:7-Hydroxy-N-(4-hydroxyphenyl)-3-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

Deprotection of the silyloxy group is carried out according to theprocess of Step D of Example 1.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 67.66 5.68 7.34 4.64 Found 67.02 5.27 7.364.61

High-resolution mass (ESI+):

C₄₃H₄₃N₄O₇  Empirical formula:

[M+H]⁺ calculated: 727.3132

[M+H]⁺ measured: 727.3121

EXAMPLE 114N-(3-Fluoro-4-methylphenyl)-N-(4-hydroxyphenyl)-3-(5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 6, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-fluoro-4-methylaniline.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 69.05 6.06 7.32 4.63 Found 68.90 5.56 7.334.41

EXAMPLE 1153-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2-fluorophenyl)-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C by4-{[tert-butyl(dimethyl)silyl]oxy}-N-(2-fluorophenyl)aniline.

High-resolution mass (ESI+):

C₄₂H₄₀ClN₄O₄  Empirical formula:

[M+H]⁺ calculated: 719.2722

[M+H]⁺ measured: 719.2802

EXAMPLE 1163-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-fluorophenyl)-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C by4-{[tert-butyl(dimethyl)silyl]oxy}-N-(3-fluorophenyl)aniline.

High-resolution mass (ESI+):

C₄₂H₄₀ClN₄O₄  Empirical formula:

[M+H]⁺ calculated: 719.2722

[M+H]⁺ measured: 719.2819

EXAMPLE 1173-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2,4-difluorophenyl)-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2,4-difluoroaniline.

High-resolution mass (ESI+):

C₄₂H₃₉ClF₂N₄O₄  Empirical formula:

[M+H]⁺ calculated: 737.2628

[M+H]⁺ measured: 737.2660

EXAMPLE 1183-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3,4-difluorophenyl)-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C by N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3,4-difluoroaniline.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 65.20 5.21 7.24 4.58 Found 65.26 5.01 6.904.57

EXAMPLE 1193-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-cyanophenyl)-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C by3-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]benzonitrile.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 67.71 5.42 9.18 4.65 Found 67.00 5.20 8.894.54

EXAMPLE 120N-(4-Hydroxyphenyl)-6-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenylpyrrolo[1,2-a]-pyrazine-8-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1 used in Step A by the compound of Preparation 31.

High-resolution mass (ESI+):

C₄₂H₃₇N₅O₆  Empirical formula:

[M+H]⁺ calculated: 708.2822

[M+H]⁺ measured: 708.2788

EXAMPLE 121N-(3-Fluorophenyl)-N-(4-hydroxyphenyl)-6-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)pyrrolo-[1,2-a]pyrazine-8-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 31, and on the other hand the compound of Preparation 1″used in Step C by4-{[tert-butyl(dimethyl)silyl]oxy}-N-(3-fluorophenyl)aniline.

High-resolution mass (ESI+):

C₄₂H₃₆FN₅O₆  Empirical formula:

[M+H]⁺ calculated: 726.2728

[M+H]⁺ measured: 726.2723

EXAMPLE 122N-(3-Fluorophenyl)-N-(4-hydroxyphenyl)-3-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1″ used in Step C by4-{[tert-butyl(dimethyl)silyl]oxy}-N-(3-fluorophenyl)aniline.

High-resolution mass (ESI+):

C₄₃H₄₁FN₄O₆  Empirical formula:

[M+H]⁺ calculated: 729.3088

[M+H]⁺ measured: 729.3068

EXAMPLE 123N-(4-Hydroxyphenyl)-3-(6-{[(3S)-3-{[4-(methylsulphonyl)piperazin-1-yl]methyl}-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1′ used in Step A by the compound of Preparation 13′.

Elemental microanalysis:

% C % H % N % S % Cl⁻ Calculated 64.11 5.62 8.50 3.89 4.30 Found 64.195.07 8.52 3.87 4.02

EXAMPLE 1243-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxyphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-methoxyaniline.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 67.27 5.78 7.30 4.62 Found 67.54 5.35 7.324.62

EXAMPLE 1253-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3,5-difluorophenyl)-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C by N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3,5-difluoroaniline.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 65.20 5.21 7.24 4.58 Found 65.85 4.93 7.044.76

EXAMPLE 1263-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(3-methylphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-methylaniline.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 68.70 5.90 7.45 4.72 Found 68.94 5.72 7.214.84

EXAMPLE 127N-(4-Hydroxyphenyl)-N-phenyl-3-(6-{[(3S)-3-{[4-(2,2,2-trifluoroethyl)-piperazin-1-yl]methyl}-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1′ used in Step A by the compound of Preparation 14′.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 65.25 5.48 8.45 4.28 Found 64.91 5.23 8.374.96

EXAMPLE 128N-(4-Hydroxyphenyl)-3-(6-{[(3S)-3-[(4-methyl-3-oxopiperazin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1′ used in Step A by the compound of Preparation 10′.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 68.25 5.73 9.04 4.58 Found 68.04 5.09 8.824.64

EXAMPLE 1293-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-cyanophenyl)-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C by4-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]benzonitrile.

Elemental microanalysis

% C % H % N Calculated 67.71 5.42 9.18 Found 68.17 5.15 8.71

EXAMPLE 1303-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N,N-diphenyl-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C by N-phenylaniline.

High-resolution mass (ESI+):

C₄₂H₄₀Cl₂N₄O₄  Empirical formula:

[M+H]⁺ calculated: 735.2427

[M+H]⁺ measured: 735.2524

EXAMPLE 1313-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-chlorophenyl)-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-chloroaniline.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 65.33 5.35 7.26 4.59 Found 64.08 5.29 6.924.59

EXAMPLE 1323-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(pyrimidin-2-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)pyrimidin-2-amine.

Elemental microanalysis:

% C % H % N Calculated 64.95 5.45 11.36 Found 64.62 5.07 10.92

EXAMPLE 1333-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(cyclobutylmethyl)-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C by4-{[tert-butyl(dimethyl)silyl]oxy}-N-(cyclobutylmethyl)aniline.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 68.16 6.39 7.76 3.93 Found 68.69 5.93 7.453.81

EXAMPLE 1343-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2-cyanophenyl)-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C by2-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]benzonitrile.

Elemental microanalysis:

% C % H % N Calculated 67.71 5.42 9.18 Found 67.34 4.95 8.73

EXAMPLE 1353-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-pyrazol-4-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 64.77 5.71 11.33 4.78 Found 64.62 5.3310.71 4.10

EXAMPLE 1363-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(cyclopropylmethyl)-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C by4-{[tert-butyl(dimethyl)silyl]oxy}-N-(cyclopropylmethyl)aniline.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 67.13 6.20 7.83 4.95 Found 67.58 5.79 7.364.16

EXAMPLE 1373-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(1-methyl-1H-pyrazol-3-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-pyrazol-3-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 64.77 5.71 11.33 4.78 Found 64.20 5.4710.78 5.27

EXAMPLE 138N-(But-2-yn-1-yl)-3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C by4-{[tert-butyl(dimethyl)silyl]oxy}-N-(but-2-yn-1-yl)aniline.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 64.95 5.45 11.36 4.79 Found 65.53 5.1910.88 5.38

EXAMPLE 1393-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(pyridin-2-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)pyridin-2-amine.

Elemental microanalysis:

% C % H % N Calculated 66.66 5.59 9.48 Found 67.12 5.37 9.11

EXAMPLE 1403-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(pyridazin-3-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)pyridazin-3-amine.

High-resolution mass (ESI+):

C₄₂H₃₉ClN₆O₄  Empirical formula:

[M+H]⁺ calculated: 703.2721

[M+H]⁺ measured: 703.2783

EXAMPLE 1413-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(pyrimidin-5-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)pyrimidin-5-amine.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 68.32 5.59 11.95 5.04 Found 68.05 5.5211.83 5.50

EXAMPLE 1423-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(pyridin-3-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamidebis(hydrochloride)

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)pyridin-3-amine.

High-resolution mass (ESI+):

C₄₁H₄₀ClN₅O₄  Empirical formula:

[M+H]⁺ calculated: 702.2769

[M+H]⁺ measured: 702.2858

EXAMPLE 1433-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3,5-difluoro-4-methoxyphenyl)-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3,5-difluoro-4-methoxyaniline.

High-resolution mass (ESI+):

C₄₃H₄₁ClF₂N₄O₅  Empirical formula:

[M+H]⁺ calculated: 767.2734

[M+H]⁺ measured: 767.2804

EXAMPLE 1443-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(pyridin-4-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamidebis(hydrochloride)

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)pyridin-4-amine.

High-resolution mass (ESI+):

C₄₁H₄₀ClN₅O₄  Empirical formula:

[M+H]⁺ calculated: 702.2842

[M+H]⁺ measured: 702.2842

EXAMPLE 1453-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-fluoro-4-methoxyphenyl)-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-fluoro-4-methoxyaniline.

High-resolution mass (ESI+):

C₄₃H₄₂ClFN₄O₅  Empirical formula:

[M+H]⁺ calculated: 749.2828

[M+H]⁺ measured: 749.2878

EXAMPLE 146N-(4-Hydroxyphenyl)-3-(6-{[(3S)-3-{[(2-methoxyethyl)(methyl)amino]-methyl}-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1′ used in Step A by the compound of Preparation 11′.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 68.93 6.05 7.48 4.73 Found 68.84 5.85 7.564.60

EXAMPLE 1473-(6-{[(3S)-3-[(1,1-Dioxidothiomorpholin-4-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(4-hydroxyphenyl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1′ used in Step A by the compound of Preparation 15′.

Elemental microanalysis:

% C % H % N % S % Cl⁻ Calculated 64.94 5.45 7.04 4.03 4.46 Found 65.275.13 7.14 3.90 4.30

EXAMPLE 148N-(5-Hydroxypyrimidin-2-yl)-3-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamidetrifluoroacetate Step A:N-[5-(Benzyloxy)pyrimidin-2-yl]-3-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide

The procedure is as in Steps A, B and C of the process of Example 1,replacing the compound of Preparation 1″ used in Step C by5-(benzyloxy)-N-phenylpyrimidin-2-amine.

Step B:N-(5-Hydroxypyrimidin-2-yl)-3-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamidetrifluoroacetate

The compound of Step A (150 mg; 0.2 mmol) is dissolved in 8 mL ofmethanol, and 30 mg of Pd/C (10% by mass palladium) are added. Thereaction mixture is stirred under a hydrogen atmosphere (1.2 bar) for 15hours and is then filtered over a Whatman filter, concentrated in vacuoand purified by reverse-phase chromatography (gradient:acetonitrile/water in the presence of trifluoroacetic acid). The desiredproduct is obtained in the form of a trifluoroacetate salt.

High-resolution mass (ESI+):

C₄₁H₄₀N₆O₆  Empirical formula:

[M+H]⁺ calculated: 713.3082

[M+H]⁺ measured: 713.3080

EXAMPLE 149N-(4-Hydroxyphenyl)-3-(6-{[(3S)-3-[(3-methoxypyrrolidin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1′ used in Step A by the compound of Preparation 16′.

Elemental microanalysis:

% C % H % N % Cl⁻ Calculated 69.42 5.96 7.36 4.66 Found 70.19 5.48 7.224.53

EXAMPLE 1503-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-cyano-4-methoxyphenyl)-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C by5-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-2-methoxybenzonitrile.

High-resolution mass (ESI+):

C₄₄H₄₂ClN₅O₅  Empirical formula:

[M+H]⁺ calculated: 756.2874

[M+H]⁺ measured: 756.2917

EXAMPLE 151N-(4-Hydroxyphenyl)-3-(5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 6, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(diméthyl)silyl]oxy}phényl)-1-méthyl-1H-pyrazol-4-amine.

High-resolution mass (ESI+):

C₄₁H₄₄N₆O₅  Empirical formula:

[M+H]⁺ calculated: 701.3446

[M+H]⁺ measured: 701.3446

EXAMPLE 1523-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-[3-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 3, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-(trifluoromethyl)aniline.

High-resolution mass (ESI+):

C₄₃H₄₀ClF₃N₄O₄  Empirical formula:

[M+H]⁺ calculated: 769.2690

[M+H]⁺ measured: 769.2718

EXAMPLE 1533-(6-{[(3S)-3-[(3,3-Difluoropyrrolidin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(4-hydroxyphenyl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1′ used in Step A by the compound of Preparation 17′.

Elemental microanalysis:

% C % H % N Calculated 67.31 5.39 7.30 Found 68.07 5.60 7.23

EXAMPLE 154N-(4-Hydroxyphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-3-(7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-2,3-dihydro-1,4-benzodioxin-6-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 7, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(diméthyl)silyl]oxy}phényl)-1-méthyl-1H-pyrazol-4-amine.

EXAMPLE 155N-(4-Hydroxyphenyl)-3-(7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-2,3-dihydro-1,4-benzodioxin-6-yl)-N-(pyrimidin-5-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 7, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)pyrimidin-5-amine.

EXAMPLE 156N-(4-Hydroxyphenyl)-3-(6-{[(3S)-3-[(3-methoxyazetidin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1′ used in Step A by the compound of Preparation 18′.

Microanalyse élémentaire:

% C % H % N Calculated 72.66 5.96 7.88 Found 72.32 5.51 7.96

High-resolution mass (ESI+):

C₄₃H₄₂N₄O₆  Empirical formula:

[M+H]⁺ calculated: 711.3177

[M+H]⁺ measured: 711.3178

EXAMPLE 1573-(6-{[(3S)-3-[(3-Fluoroazetidin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(4-hydroxyphenyl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing the compoundof Preparation 1′ used in Step A by the compound of Preparation 19′.

EXAMPLE 1583-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 4, and on the other hand the compound of Preparation 1″ usedin Step C byN-(4-{[tert-butyl(diméthyl)silyl]oxy}phényl)-1-méthyl-1H-pyrazol-4-amine.

EXAMPLE 1593-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(1-methyl-1H-pyrazol-4-yl)indolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 32, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(diméthyl)silyl]oxy}phényl)-1-méthyl-1H-pyrazol-4-amine.

EXAMPLE 1603-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(1-methyl-1H-pyrazol-4-yl)indolizine-1-carboxamidehydrochloride

The procedure is as in the process of Example 1, replacing on the onehand the compound of Preparation 1 used in Step A by the compound ofPreparation 14, and on the other hand the compound of Preparation 1″used in Step C byN-(4-{[tert-butyl(diméthyl)silyl]oxy}phényl)-1-méthyl-1H-pyrazol-4-amine.

Pharmacological Study Example A Inhibition of Bcl-2 by the FluorescencePolarisation Technique

The fluorescence polarisation tests were carried out on microplates (384wells). The Bcl-2 protein, at a final concentration of 2.50×10⁻⁸ M, ismixed with a fluorescent peptide (Fluorescein-REIGAQLRRMADDLNAQY), at afinal concentration of 1.00×10⁻⁸ M in a buffer solution (Hepes 10 mM,NaCl 150 mM, Tween20 0.05%, pH 7.4), in the presence or in the absenceof increasing concentrations of test compounds. After incubation for 2hours, the fluorescence polarisation is measured.

The results are expressed in IC₅₀ (the concentration of compound thatinhibits fluorescence polarisation by 50%) and are presented in Table 1below.

The results show that the compounds of the invention inhibit interactionbetween the Bcl-2 protein and the fluorescent peptide describedhereinbefore.

Example B In Vitro Cytotoxicity

The cytotoxicity studies were carried out on the RS4;11 leukaemia tumourline.

The cells are distributed onto microplates and exposed to the testcompounds for 48 hours.

The cell viability is then quantified by a colorimetric assay, theMicroculture Tetrazolium Assay (Cancer Res., 1987, 47, 939-942).

The results are expressed in IC₅₀ (the concentration of compound thatinhibits cell viability by 50%) and are presented in Table 1 below.

The results show that the compounds of the invention are cytotoxic.

TABLE 1 IC₅₀ of Bcl-2 inhibition (fluorescence polarisation test) and ofcytotoxicity for RS4; 11 cells IC₅₀ (nM) Bcl-2 FP IC₅₀ (nM) MTT RS4; 11Example 1 18 60.1 Example 2 20 49.8 Example 3 20 44.7 Example 4 19 27.1Example 5 51 98 Example 6 15 30 Example 8 15 25.6 Example 9 13 16.1Example 10 18 11 Example 13 12 8.63 Example 14 16 10.7 Example 15 1720.4 Example 16 18 23.4 Example 17 81 120 Example 18 32 24.9 Example 1927 42.3 Example 20 35 105 Example 21 22 34.6 Example 22 27 19.1 Example23 14 23 Example 24 17 29.8 Example 25 29 143 Example 26 17 40 Example27 17 35.4 Example 28 25 76.1 Example 29 35 85.5 Example 30 13 8.59Example 31 33 340 Example 32 34 71.3 Example 33 23 12.2 Example 34 2765.8 Example 35 15 11.7 Example 36 43 135 Example 37 19 11.6 Example 3821 61.8 Example 39 16 14.1 Example 40 15 32.2 Example 41 26 44 Example42 13 53.6 Example 43 110 142 Example 44 14 45 Example 45 47 76.8Example 46 21 56.8 Example 47 58 194 Example 48 130 229 Example 49 45169 Example 50 13 4.01 Example 51 32 26 Example 52 16 19.8 Example 53180 138 Example 54 180 106 Example 55 34 19.4 Example 56 20 25.9 Example57 12 8.62 Example 58 22 40.1 Example 59 13 8.13 Example 60 19 11.7Example 61 22 14.5 Example 62 22 19.3 Example 63 21 18.8 Example 64 3123.3 Example 65 14 9.19 Example 66 16 21.7 Example 67 24 17.7 Example 6926 16.7 Example 70 19 14 Example 71 21 24.4 Example 72 220 270 Example74 24 241 Example 76 17 49 Example 77 23 70.4 Example 78 31 101 Example79 31 67.5 Example 80 18 18.8 Example 81 28 39.3 Example 82 33 21.9Example 83 18 41.2 Example 84 18 20.6 Example 85 41 246 Example 86 2229.5 Example 87 27 121 Example 91 8 65.5 Example 92 5 40.2 Example 94 38.16 Example 95 6 13.5 Example 96 11 58.8 Example 97 20 45.4 Example 9812 73.5 Example 99 25 213 Example 100 22 856 Example 101 5 22.1 Example103 6 16.8 Example 104 7 21.6 Example 105 10 28.9 Example 107 7 8.29Example 108 9 36.4 Example 109 30 483 Example 110 29 129 Example 111 1581.5 Example 112 9 139 Example 113 16 190 Example 114 9 43.1 Example 1158 58.1 Example 116 10 43.6 Example 117 15 194 Example 118 15 71 Example119 9 31.6 Example 121 34 445 Example 122 16 43.5 Example 123 22 92.1Example 124 28 101 Example 125 38 81.8 Example 126 26 115 Example 127 26129 Example 128 10 63.4 Example 129 9 46.7 Example 131 30 88.4 Example134 37 305 Example 135 6 37.4 Example 141 n.d. 72.5 Example 142 n.d.66.1 Example 143 n.d. 43.8 Example 144 n.d. 59.9 Example 145 n.d. 28.9Example 146 n.d. 153 Example 147 n.d. 74.2

Example C Induction of Caspase Activity In Vivo

The ability of the compounds of the invention to activate caspase 3 isevaluated in a xenograft model of RS4;11 leukaemia cells.

1×10⁷ RS4;11 cells are grafted sub-cutaneously into immunosuppressedmice (SCID strain). 25 to 30 days after the graft, the animals aretreated orally with the various compounds. Sixteen hours aftertreatment, the tumour masses are recovered and lysed, and the caspase 3activity is measured in the tumour lysates.

This enzymatic measurement is carried out by assaying the appearance ofa fluorigenic cleavage product (DEVDase activity, Promega). It isexpressed in the form of an activation factor corresponding to the ratiobetween the two caspase activities: the activity for the treated micedivided by the activity for the control mice.

The results obtained are presented in Table 2 and show that thecompounds of the invention are capable of inducing apoptosis in RS4;11tumour cells in vivo.

TABLE 2 Caspase activation factors (DEVDase activity in the tumours oftreated mice versus control mice) in vivo, after oral treatment (exactdoses in brackets) Activation factor Compound tested (versus control)Example 1 29.3 (100 mg/kg) Example 2 27.8 (100 mg/kg) Example 3  5.7 (50mg/kg) Example 4 29.2 (50 mg/kg) Example 8  9.8 (50 mg/kg) Example 920.6 (50 mg/kg) Example 10 13.8 (50 mg/kg) Example 22 11.3 (50 mg/kg)Example 23 22.7 (50 mg/kg) Example 58 23.3 (50 mg/kg) Example 59   23(50 mg/kg) Example 66 24.7 (50 mg/kg) Example 67 18.9 (50 mg/kg)

Example D Quantification of the Cleaved Form of Caspase 3 In Vivo

The ability of the compounds of the invention to activate caspase 3 isevaluated in a xenograft model of RS4;11 leukaemia cells.

1×10⁷ RS4;11 cells are grafted sub-cutaneously into immunosuppressedmice (SCID strain). 25 to 30 days after the graft, the animals aretreated orally with the various compounds. After treatment, the tumourmasses are recovered and lysed, and the cleaved (activated) form ofcaspase 3 is quantified in the tumour lysates.

The quantification is carried out using the “Meso Scale Discovery (MSD)ELISA platform” test, which specifically assays the cleaved form ofcaspase 3. It is expressed in the form of an activation factorcorresponding to the ratio between the quantity of cleaved caspase 3 inthe treated mice divided by the quantity of cleaved caspase 3 in thecontrol mice.

The results obtained are presented in Table 3 and show that thecompounds of the invention are capable of inducing apoptosis in RS4;11tumour cells in vivo.

TABLE 3 Caspase activation factors (cleaved caspase 3 MSD test in thetumours of treated mice versus control mice) in vivo, after oraltreatment (exact doses in brackets) Activation factor Compound tested(versus control) Example 78 10.4 (25 mg/kg) Example 87 18.3 (50 mg/kg)Example 122 17.4 (25 mg/kg) Example 135   60 (50 mg/kg)

Example E Anti-Tumour Activity In Vivo

The anti-tumour activity of the compounds of the invention is evaluatedin a xenograft model of RS4;11 leukaemia cells.

1×10⁷ RS4;11 cells are grafted sub-cutaneously into immunosuppressedmice (SCID strain). 25 to 30 days after the graft, when the tumour masshas reached about 150 mm³, the mice are treated orally with the variouscompounds in two different regimes (daily treatment for five days perweek for two weeks, or two treatments weekly for two weeks). The tumourmass is measured twice weekly from the start of treatment.

The compounds of the invention have anti-tumour activities, by the oralroute, in the RS4;11 leukaemia model (acute lymphoblastic leukaemia)with ΔT/C (qualification parameter of the activity of a product, whichis defined as the ratio tumour volume of the treated group/tumour volumeof the untreated control group) ranging from −15 to −56% related totumour regression. The results obtained therefore show that thecompounds of the invention are capable of inducing significant tumourregression during the treatment period.

Example F Pharmaceutical Composition: Tablets

1000 tablets containing a dose of 5 mg of a 5 g compound selected fromExamples 1 to 160 Wheat starch 20 g  Maize starch 20 g  Lactose 30 g Magnesium stearate 2 g Silica 1 g Hydroxypropylcellulose 2 g

1. A method of treating a condition requiring a pro-apoptotic agent in asubject in need thereof, comprising administration of an effectiveamount of a compound of formula (I):

wherein: X and Y represent a carbon atom or a nitrogen atom, wherein Xand Y may not simultaneously represent two carbon atoms or two nitrogenatoms; the Het moiety of the group

 represents an optionally substituted, aromatic or non-aromatic ringcomposed of 5, 6 or 7 ring members, which ring may have, in addition tothe nitrogen represented by X or by Y, from one to 3 heteroatomsselected independently from oxygen, sulphur and nitrogen, wherein thenitrogen atom may be substituted by a hydrogen atom, a linear orbranched (C₁-C₆)alkyl group or a —C(O)—O-Alk group wherein Alk is alinear or branched (C₁-C₆)alkyl group; R₁ and R₂ independently of oneanother represent a hydrogen atom or a linear or branched (C₁-C₆)alkylgroup, or R₁ and R₂ together with the nitrogen atom carrying them form aheterocycloalkyl composed of from 4 to 7 ring members, which ring mayhave, in addition to the nitrogen atom, another heteroatom selected fromoxygen, sulphur, SO₂ and NR wherein R represents a hydrogen atom, alinear or branched (C₁-C₆)alkyl group, a (C₁-C₆)alkylsulphonyl group, alinear or branched (C₁-C₆)polyhaloalkyl group or a —C(O)—O-Alk groupwherein Alk is a linear or branched (C₁-C₆)alkyl group; R₃ represents alinear or branched (C₁-C₆)alkyl group, a (C₂-C₆)alkenyl group, a(C₂-C₆)alkynyl group, a cycloalkyl group, a(C₄-C₁₀)cycloalkyl-(C₁-C₆)alkyl group wherein the alkyl group may belinear or branched, an aryl group or a heteroaryl group; R₄ representsan aryl, heteroaryl, cycloalkyl or linear or branched (C₁-C₆)alkylgroup; R₅ represents a hydrogen atom or a halogen atom; R_(a), R_(b),R_(c) and R_(d) independently of one another represent a hydrogen atom,a halogen atom, a linear or branched (C₁-C₆)alkyl group, a linear orbranched (C₁-C₆)alkoxy group, a hydroxy group, a linear or branched(C₁-C₆)polyhaloalkyl group, or a trifluoromethoxy group, or thesubstituents of one of the pairs (R_(a),R_(b)), (R_(b),R_(c)) or(R_(c),R_(d)) together with the carbon atoms carrying them form a ringcomposed of from 5 to 7 ring members, which ring may have from one to 3heteroatoms selected from oxygen, sulphur and nitrogen, wherein thenitrogen atom may be substituted by a hydrogen atom, a linear orbranched (C₁-C₆)alkyl group or a —C(O)—O-Alk group wherein Alk is alinear or branched (C₁-C₆)alkyl group, wherein one or more carbon atomsof the ring defined hereinbefore may be deuterated, it being understoodthat: “aryl” means a phenyl, naphthyl, biphenyl or indenyl group,“heteroaryl” means any mono- or bi-cyclic group composed of from 5 to 10ring members, having at least one aromatic moiety and containing from 1to 3 hetero atoms selected from oxygen, sulphur and nitrogen,“cycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic groupcontaining from 4 to 10 ring members, wherein the alkyl, aryl,heteroaryl, cycloalkyl and heterocycloalkyl groups so defined may beoptionally substituted by from 1 to 3 groups selected from optionallysubstituted linear or branched (C₁-C₆)alkyl, (C₃-C₆)spiro, linear orbranched (C₁-C₆)alkoxy, (C₁-C₆)alkyl-S—, hydroxy, oxo (or N-oxide whereappropriate), nitro, cyano, —COOR′, NR′R″, linear or branched(C₁-C₆)polyhaloalkyl, trifluoromethoxy, (C₁-C₆)alkylsulphonyl orhalogen, wherein R′ and R″ independently of one another represent ahydrogen atom or a linear or branched (C₁-C₆)alkyl group, and whereinthe Het moiety of the group defined hereinbefore may be optionallysubstituted by a group selected from linear or branched (C₁-C₆)alkyl,hydroxy, NR₁′R₁″ and halogen, wherein R₁′ and R₁″ independently of oneanother represent a hydrogen atom or a linear or branched (C₁-C₆)alkylgroup, or an enantiomer, a diastereoisomer, or an addition salt thereofwith a pharmaceutically acceptable acid or base.
 2. The method accordingto claim 1, wherein the group

represents one of the following groups: 5,6,7,8-tetrahydroindolizineoptionally substituted by a hydroxy, indolizine,1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine, tert-butyl3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate,3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine, 2,3-dihydro-1H-pyrrolizineoptionally substituted by a hydroxy,6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine or pyrrolo[1,2-a]pyrazine.3. The method according to claim 1, wherein R₁ and R₂ each represents analkyl group optionally substituted by a methoxy, or R₁ and R₂ togetherwith the nitrogen atom carrying them form a heterocycloalkyl selectedfrom the following groups: morpholine optionally substituted by one ormore linear or branched (C₁-C₆)alkyl(s), oxidomorpholine, thiomorpholine1,1-dioxide, 1,4-oxazepan, 3-methoxypyrrolidine,3,3-difluoropyrrolidine, 3-methoxyazetidine, 3-fluoroazetidine,oxopiperazine or piperazine, the last two groups being substituted by alinear or branched (C₁-C₆)alkyl group, linear or branched(C₁-C₆)-polyhaloalkyl group or methylsulphonyl group.
 4. The methodaccording to claim 1, wherein R_(a) and R_(d) each represents a hydrogenatom, and (R_(b),R_(c)) together with the carbon atoms carrying themform a 1,3-dioxolane group wherein one of the carbon atoms is optionallydeuterated, a 1,4-dioxane group, or a 1,4-dioxepane group; or R_(a),R_(c) and R_(d) each represents a hydrogen atom and R_(b) represents ahalogen, a methyl, a methoxy, an ethoxy, a trifluoromethyl or atrifluoromethoxy.
 5. The method according to claim 1, wherein R₄represents a 4-hydroxyphenyl group, a 3-fluoro-4-hydroxyphenyl group ora 5-hydroxypyrimidine group.
 6. The method according to claim 1, whereinR₃ represents a group selected from phenyl, indole, indoline,1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-1,4-benzoxazine, indane,1H-indazole, 1H-pyrrolo[2,3-b]pyridine, pyrimidine, cyclobutylmethyl,cyclopropylmethyl, 1H-pyrazole, pyridine, and pyridazine, which groupsmay optionally have one or more substituents selected from halogen,linear or branched (C₁-C₆)alkyl, cyano and linear or branched(C₁-C₆)alkoxy.
 7. The method according to claim 1, wherein the compoundof formula (I) is selected from:N-(4-hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-N-phenyl-5,6,7,8-tetrahydro-1-indolizinecarboxamide,3-{5-chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)-carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide,N-(4-hydroxyphenyl)-N-(1-methyl-1H-indazol-5-yl)-3-{2,2-dideuterio-6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide,N-(4-hydroxyphenyl)-N-(1-methyl-1H-indazol-5-yl)-3-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamide,N-(4-hydroxyphenyl)-3-{7-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-2,3-dihydro-1,4-benzodioxin-6-yl}-N-phenyl-5,6,7,8-tetrahydro-1-indolizinecarboxamide,N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-3-{6-[((3S)-3-[(4-methyl-1-piperazinyl)methyl]-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-1-indolizinecarboxamide,N-[4-(hydroxy)phenyl]-N-(1-methyl-1H-indol-5-yl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide,N-(4-hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-N-phenyl-1-indolizinecarboxamide,3-{5-chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-1-indolizinecarboxamide,6-{5-chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)-carbonyl]phenyl}-N-(3-fluoro-4-methylphenyl)-N-(4-hydroxyphenyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide,3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamide,N-(3-fluoro-4-methylphenyl)-N-(4-hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide,N-[4-(hydroxy)phenyl]-N-(1-methyl-2,3-dihydro-1H-indol-5-yl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide,3-{5-chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-2,3-dihydro-1H-indol-5-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide,N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-1-indolizinecarboxamide,3-{5-chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)-carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-2,3-dihydro-1H-indol-5-yl)-1-indolizinecarboxamide,6-{5-chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)-carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c]-[1,4]oxazine-8-carboxamide,andN-(3-fluorophenyl)-N-(4-hydroxyphenyl)-3-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamide,or an enantiomer, a diastereoisomer, or an addition salt thereof with apharmaceutically acceptable acid or base.
 8. The method according toclaim 1, wherein the compound of formula (I) is selected from:N-(4-hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-N-phenyl-5,6,7,8-tetrahydro-1-indolizinecarboxamide,3-{5-chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)-carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-5,6,7,8-tetrahydro-1-indolizinecarboxamide,N-(4-hydroxyphenyl)-N-(1-methyl-1H-indazol-5-yl)-3-{2,2-dideuterio-6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide,N-(4-hydroxyphenyl)-N-(1-methyl-1H-indazol-5-yl)-3-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamide,N-(4-hydroxyphenyl)-3-{7-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-2,3-dihydro-1,4-benzodioxin-6-yl}-N-phenyl-5,6,7,8-tetrahydro-1-indolizinecarboxamide,N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-3-{6-[((3S)-3-[(4-methyl-1-piperazinyl)methyl]-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-1-indolizinecarboxamide,N-[4-(hydroxy)phenyl]-N-(1-methyl-1H-indol-5-yl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-5,6,7,8-tetrahydro-1-indolizinecarboxamide,N-(4-hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-N-phenyl-1-indolizinecarboxamide,3-{5-chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-1-indolizinecarboxamide,6-{5-chloro-2-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)-carbonyl]phenyl}-N-(3-fluoro-4-methylphenyl)-N-(4-hydroxyphenyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide,and3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamide,or an enantiomer, a diastereoisomer, or an addition salt thereof with apharmaceutically acceptable acid or base.
 9. The method according toclaim 1, wherein the compound of formula (I) is administered as apharmaceutical composition comprising the compound of formula (I) incombination with one or more pharmaceutically acceptable excipients. 10.The method according to claim 1, wherein the condition is selected fromcancer, diseases of the immune system, and auto-immune diseases.
 11. Themethod according to claim 10, wherein the condition is cancer.
 12. Themethod according to claim 11, wherein the condition is selected fromcancer of the bladder, brain, breast and uterus, chronic lymphoidleukaemias, cancer of the colon, oesophagus and liver, lymphoblasticleukaemias, follicular lymphomas, melanomas, malignant haemopathies,myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancerand small-cell lung cancer.
 13. The method according to claim 11,wherein the compound of formula I is administered in combination with ananti-cancer agent selected from genotoxic agents, mitotic poisons,anti-metabolites, proteasome inhibitors, kinase inhibitors andantibodies.
 14. The method according to claim 11, wherein the compoundof formula I is administered in combination with radiotherapy.